Triazine derivative, production and use thereof

ABSTRACT

The present invention provides a novel triazine derivative of the formula                    
     wherein ring A is an optionally substituted aromatic group which be; 
     X is an oxygen or sulfur atom; 
     R 1  and R 6  are each a hydrogen atom or an optionally substituted hydrocarbon residue or heterocyclic group which may bound through a hetero-atom; 
     R 2  and R 3  are each independently a hydrogen atom, a halogen atom, or a group bound through a carbon, oxygen or sulfur atom, or taken together, represent ═S; 
     R 4  and R 5  are each independently a hydrogen atom, a halogen atom, or a group bound through a carbon, oxygen, nitrogen or sulfur atom; 
     R 1  and R 2 , and R 5  and R 6 , may each bind together to form a chemical bond; provided that where ring A is a phenyl group having at least a halogen atom in position-2 or 4 and X is an oxygen atom, R 4  and R 5  do not conjoinedly represent a chemical bond and an antiprotozoan composition containing the same or salt thereof.

This application is a divisional of application Ser. No. 08/810,499,filed Feb. 28, 1997, now U.S. Pat. No. 5,994,355, which is acontinuation of application Ser. No. 08/755,059, filed Nov. 22, 1996,now abandoned, which is a continuation-in-part of application Ser. No.08/632,580, filed Apr. 15, 1996, now abandoned, and Ser. No. 08/602,451,filed Feb. 16, 1996, now abandoned, which in turn is a continuation ofapplication Ser. No. 08/322,489, filed Oct. 14, 1994, now abandoned.

FIELD OF THE FIRST EMBODIMENT

The first embodiment relates to a novel triazine derivative or a saltthereof, an uses for them. More particularly, the first embodimentrelates to the novel triazine derivatives or a salt thereof, which isuseful for controlling parasitic protozoa, particularly for coccidia andthe like, and an antiprotozoan composition comprising them.

BACKGROUND OF THE FIRST EMBODIMENT

Parasitic protozoa are parasites on a broad range of animals inclusiveof mammals, birds, fishes and insects. The parasitic protozoa establishthemselves in the internal organs or the external organs such as theskin and eye of the host animal. As such, these parasites give the hostsserious lesion and often infect the producing farmers of domesticanimals, poultry and fish, causing great economic damage. Coccidiosis,which is one of the diseases causing the most serious economic damage tobreeding, is mainly caused by several kinds of protozoa of the genusEimeria, such as E. tenella, E. necatrix, E. acervulira, E. maxima, E.brunetti and E. mivati.

For example, E. tenella parasitizes the intestinal inner walls, such asthat of the caecum, and often inflicts fatal damage on the host. Thus,the E. tenella infection produces several manifestations such asextensive erosion, inflammation and hemorrhage of the intestinal pariesdue to the development of the protozoa, caecal blood retention, and,hence, anaemia, retardation of growth or death of the host. Endoparasticprotozoa are usually transmitted orally and as to coccidiosis inparticular, even intensive disinfection with potassium dichromatesolution fails to kill the oocysts. Moreover, since their life cycle isas short as about 7 days, one engaged in large-scale animal farming hasto face the outbreak and spread of disease without an effectivecountermeasure.

As far as fishes are concerned, ectoparasitic protozoa are seriousproblems of concern. Their para-sitization damages the host's skin andgills, weakens the resistance of the host fish to infections and mayoccasionally be fatal. In large-scale fish farming, parasitic protozoaspread among the whole fish population on a farm and the resultingeconomic loss is too large to be overlooked.

A similar situation prevails for insects. Taking bees as an example,parasitic protozoan represented by Nosema apis are doing a great deal ofharm to apiculture all over the world. Nosema apis destroys the internalorgans to debilitate the host bee, and the host with accordinglydecreased resistance tends to succumb to various other diseases.

Several drugs against parasitic protozoa have been proposed but most ofthem are limited in the indication and spectrum of activity and evenprotozoa with acquired resistance to certain drugs are already known.Furthermore, the weak activity of these drugs requires massive doses sothat none are satisfactory enough from both economic and ecologicalpoints of view. Therefore, development of drugs which can be usedbroadly with sufficient effectiveness for control of such parasites inanimals, poultry, fishes and insects are awaited in earnest.

As such drugs, 2-phenyl-6-azauracil derivatives were found to have ananticoccidial activity [J. Med. Chem. 22, 1483 (1979)] and a variety of6-azauracil derivatives were synthesized and tested. However, thesecompounds were found to be teratogenic and, therefore, could not findapplication in the field. As compounds which overcame the problemsrelated to the teratogenicity, 1,2,4-triazinediones are in use in someEuropean countries, Australia and Hungary or South Africa asanticoccidial drugs. However, since these compounds remain in the bodyin long time their use is critically restricted and even banned inseveral countries including Japan.

In view of above state of the art, the present inventors have researchedand found that a series of novel triazine derivatives have excellentactivity against parasitic protozoa. Further intensive research led themto the discovery that this series of derivatives is suited for thecontrol of a broad spectrum of parasitic protozoa encountered in rearingand raising animals such as mammals, birds, fish and insects under theusual husbandry and breeding conditions, are of low toxicity to animals,and exhibit remarkably high antiprotozoal activity even against strainsresistant to the drugs heretofore available. This first embodiment hasbeen brought into being on the basis of the above findings.

THE SUMMARY OF THE FIRST EMBODIMENT

The first embodiment is directed to:

(1) a triazine derivative of the formula

 wherein ring A is an optionally substituted aromatic group;

X is an oxygen or sulfur atom;

R¹ and R⁶ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon residue or heterocyclic group which may boundthrough a hetero-atom;

R² and R³ are each independently a hydrogen atom, a halogen atom, or agroup bonding through a carbon, oxygen or sulfur atom, or, takentogether, represent ═S;

R⁴ and R⁵ are each independently a hydrogen atom, a halogen atom, or agroup bound through a carbon, oxygen, nitrogen or sulfur atom;

R¹ and R², and R⁵ and R⁶ taken together may form a chemical bond;provided that where ring A is a phenyl group having at least a halogenatom in positions 2 or 4 and X is an oxygen atom, R⁵ and R⁶ do not bindtogether to form a chemical bond or salt thereof,

(2) an antiprotozoan composition comprising an effective amount of thetriazine derivative or salt mentioned above (1) and a physiologicallyacceptable carrier, excipient or diluent. (3) a feed additive whichcomprises the triazine derivatives or a salt thereof as mentioned above,and (4) a method of rearing and breeding animals which comprisesadministering an effective amount of the triazine derivatives or a saltmentioned above. The first embodiment also relates to (5) a method ofpreparing the triazine derivatives, or the antiprotozoal composition.

Referring to the above formula, the optionally substituted aromaticgroup, ring A, includes 5 to 6-membered homo- or hetero-aromatic groupswhich may have one or more substituents.

The carbocycle of said optionally substituted homoaromatic group may forexample be benzene.

The heteroaromatic group includes 5- or 6-membered unsaturatedheterocyclic groups containing 1 to 4 hetero-atoms selected from amongoxygen, sulfur, nitrogen and the like in addition to at least one carbonatom, for example 5-membered heterocyclic groups containing 1 to 4hetero-atoms selected from among oxygen, sulfur, nitrogen and the likein addition to at least one carbon atom, such as 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl,3-, 4- or 5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl),1,3,4-oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-or 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc., and 6-membered heterocyclicgroups containing 1 to 4 hetero-atoms selected from among oxygen,sulfur, nitrogen and the like in addition to at least one carbon atom,such as 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, oxoimidazinyl,dioxotriazinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,1,3-thiazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl,N-oxide-3- or 4-pyridazinyl, etc. Among them, 6-membered heterocyclicgroups having one hetero-atom as a ring member are preferred andnitrogen-containing heterocyclic groups are particularly desirable.

Such a homo- or hetero-aromatic group may be substituted, in 1 to 5 orpreferably 1 to 3 substitutable positions, by the following substituentgroups, among others;

(1) C₁₋₄ alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, etc.

(2) C₂₋₄ alkenyl, e.g. vinyl, 1-methylvinyl, 1-propenyl, allyl, etc.

(3) C₂₋₄ alkinyl, e.g. ethinyl, 1-propinyl, propargyl, etc.

(4) C₃₋₆ cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.

(5) C₅₋₇ cycloalkenyl, e.g. cyclopentenyl, cyclohexenyl, etc.

(6) C₇₋₁₁ aralkyl, e.g. benzyl, α-methylbenzyl, phenethyl, etc.

(7) phenyl

(8) C₁₋₆ alkoxy, e.g. methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, etc.

(9) phenoxy

(10) C₁₋₆ alkanoyl, e.g. formyl, acetyl, propionyl, n-butyryl,iso-butyryl, etc.

(11) benzoyl

(12) C₁₋₆ alkanoyloxy, e.g. formyloxy, acetyloxy, propionyloxy,n-butyryloxy, iso-butyryloxy, etc. and benzoyloxy

(13) carboxyl

(14) C₂₋₇ alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, etc.

(15) carbamoyl

(16) N-mono-C₁₋₄ alkylcarbamoyl, e.g. N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, etc.

(17) N-di-C₁₋₄ alkylcarbamoyl, e.g. N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, etc.

(18) cycloaminocarbonyl, e.g. 1-aziridinylcarbonyl,1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl,N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.

(19) halogens, e.g. F, Cl, Br, I,etc.

(20) mono-, di- or tri-halo-C₁₋₄ alkyl, e.g. chloromethyl,dichloromethyl, trifluoromethyl, trifluoroethyl, etc.

(21) oxo

(22) amidino

(23) imino

(24) optionally protected amino (the protected group for amino group isdefined below)

(25) mono-C₁₋₄ alkylamino, e.g. methylamino, ethylamino, propylamino,isopropylamino, butylamino, etc.

(26) di-C₁₋₄ alkylamino, e.g. dimethylamino, diethylamino,dipropylamino, diisopropylamino, dibutylamino, etc.

(27) 3- to 6-membered cycloamino which may contain 1 to 3 hetero-atomsselected from among oxygen, sulfur, nitrogen, etc. in addition to atleast one carbon atom and one nitrogen atom, such as aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl,imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl,N-methylpiperazinyl, N-ethylpiperazinyl, etc.

(28) C₁₋₆ alkanamido such as formamido, acetamido, trifluoroacetamido,propionamido, butyrylamido, iso-butyrylamido, etc.

(29) benzamido

(30) carbamoylamino

(31) N—C₁₋₄ alkylcarbamoylamino, e.g. N-methylcarbamoylamino,N-ethylcarbamoylamino, N-propylcarbamoylamino,N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.

(32) N-N-di-C₁₋₄ alkylcarbamoylamino, e.g. N,N-dimethylcarbamoylamino,N,N-diethylcarbamoylamino, N,N-dipropylcarbamoylamino,N,N-dibutylcarbamoylamino, etc.

(33) C₁₋₃ alkylenedioxy, e.g. methylenedioxy, ethylenedioxy, etc.

(34) —B(OH)₂

(35) hydroxy

(36) epoxy (—O—)

(37) nitro

(38) cyano

(39) mercapto

(40) sulfo

(41) sulfino

(42) phosphono

(43) dihydroxypolyol

(44) sulfamoyl

(45) C₁₋₆ monoalkylsulfamoyl, e.g. N-methylsulfamoyl, N-ethylsulfamoyl,N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.

(46) di-C₁₋₄ alkylsulfamoyl, e.g. N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl, etc.

(47) C₁₋₆ alkylthio, e.g. methylthio, ethylthio, propylthio,isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.

(48) phenylthio

(49) C₁₋₆ alkylsulfinyl, e.g. methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, etc.

(50) phenylsulfinyl

(51) C₁₋₆ alkylsulfonyl, e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, etc.

(52) phenylsulfonyl and

(53) 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atomsselected from among oxygen, sulfur, nitrogen and the like in addition toat least one carbon atom, which may be bound through a one or two atomchain containing oxygen, sulfur, nitrogen, carbon or the like, forexample 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl, N-oxide-2-, 3- or 4-pyridyl, 2-,4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, oxoimidazinyl,dioxotriazinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,1,3-thiazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl,N-oxide-3- or 4-pyridazinyl, and so on.

Of the above-mentioned groups, any group having a carbon chain of 2 ormore C atoms or a cyclic group may be further substituted, in 1 or 2substitutable positions, by such substituent groups as

(a) halogens, e.g. Cl, F, etc.

(b) hydroxy,

(c) oxo,

(d) C₁₋₄ alkoxy, e.g. methoxy, ethoxy, etc.

(e) di-C₁₋₄ alkylamino, e.g. dimethylamino, diethylamino, etc.

(f) halo-C₁₋₄ alkyl, e.g. chloromethyl, trifluoromethyl, trifluoroethyl,etc.

(g) C₁₋₄ acyl, e.g. formyl, acetyl, etc.

(h) hydroxy-C₁₋₄ alkyl, e.g. hydroxymethyl, 2-hydroxyethyl, etc.

(i) C₁₋₄ alkoxy-C₁₋₄ alkyl, e.g. methoxymethyl, 2-ethoxyethyl etc.

(j) cyano

(k) thioxo and

(l) C₁₋₄ alkylthio, e.g. methylthio, ethylthio, propylthio,isopropylthio, n-butylthio, sec-butylthio, t-butylthio and so on.

Further, when the substitution exists on two ring-forming atoms adjacentto each other, they may bind together to form a ring. The condensed ringthus formed is a 8 to 10 membered bicyclic ring which includes bicyclicaryl group such as 1- or 2-pentalenyl, 1- or 2-indenyl (1H- or2H-indenyl) or 1-or 2-naphthylyl, and bicyclic heterocyclic ringcontaining 1 to 4 hetero atom selected from among oxygen, sulfur, ornitrogen in addition to at least one carbon atom, such as indolyl,isoindolyl, benzofuryl, benzothiophenyl, benzothiazolyl, benzoxazolyl,tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, benzimidazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolynyl,quinoxalinyl, indolidinyl, quinolidinyl, 1,8-naphthylidinyl, purinyl,putheridinyl, dibenzofuranyl, chromanyl, benzoxazinyl or like.

Among the above exemplified substituents, halogen atom, optionallysubstituted alkyl, especially C₁₋₄ alkyl group, haloalkyl group oroptionally substituted aralkyl, especially phenyl C₁₋₄ alkyl group, aphenyl or heterocyclic group which may be bound through an atomic chainof 1 or 2 atoms such as phenoxy, phenylthio, benzoyl, benzoyloxy,phenylsulfonyl, benzomide and heterocyclic group optionally boundthrough an atomic chain of 1 or 2 atoms are preferable.

In regard to substitution topology, the benzene ring, for instance, maypreferably be substituted in position 3 and/or 5, more preferably besubstituted in position 4 in addition to the substitution in 3 and/or 5but these are not exclusive choices, of course.

X represents an oxygen or sulfur atom and is preferably an oxygen atom.

Where R¹ and R⁶ are the optionally substituted hydrocarbon residues eachof which may be bound through a hetero-atom, the particular hydrocarbonresidue includes, among others, C₁₋₁₅ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, etc., C₃₋₈ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc., C₂₋₁₀ alkenyl such as vinyl, allyl,2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl, etc., C₂₋₁₀ alkinyl suchas ethinyl, 2-propinyl, 3-hexinyl, etc., C₃₋₁₀ cycloalkenyl such ascyclopropenyl, cyclopentenyl, cyclohexenyl, etc., C₆₋₁₄ aryl such asphenyl, naphthyl, etc., C₇₋₁₆ aralkyl such as benzyl, phenylethyl, etc.Among them alkyl, aryl and aralkyl group are preferable. Hydrocarbonresidues having 1 to 7 carbon atoms are also preferable. Any of suchhydrocarbon groups may have 1 to 5 substituent groups in substitutablepositions as selected from among

(1) nitro

(2) hydroxy

(3) oxo

(4) thioxo

(5) cyano

(6) carbamoyl

(7) carboxyl

(8) C₁₋₄ alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, etc.

(9) sulfo

(10) halogens, e.g. F, Cl, Br, I, etc.

(11) C₁₋₄ lower alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, s-butoxy, t-butoxy, etc.

(12) phenoxy

(13) nalophenoxy, e.g. o-, m- or p-chlorophenoxy, o-, m- orp-bromophenoxy, etc.

(14) C₁₋₄ lower alkylthio, e.g. methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, t-butylthio, etc.

(15) phenylthio

(16) C₁₋₄ lower alkylsulfinyl, e.g. methylsulfinyl, ethylsulfinyl, etc.

(17) C₁₋₄ lower alkylsulfonyl, e.g. methylsulfonyl, ethylsulfonyl, etc.

(18) amino

(19) C₁₋₆ lower acylamino, e.g. acetylamino, propionylamino, etc.

(20) mono- or di-C₁₋₄ alkylamino, e.g. methylamino, ethylamino,n-propylamino, isopropylamino, n-butylamino, dimethylamino,diethylamino, etc.

(21) C₁₋₄ lower acyl, e.g. formyl, acetyl, etc.

(22) benzoyl

(23) 5- or 6-membered heterocyclic groups containing 1 to 4 hetero-atomsselected from among oxygen, sulfur, nitrogen and the like in addition toat least one carbon atom, such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4-or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl, indolyl, etc.which may be substituted by 1 to 4 substituents selected from among (a)halogens such as Br, Cl, F, etc., (b) C₁₋₄ lower alkyl such as methyl,ethyl, propyl, isopropyl, etc. and (c) halophenoxy such as o-, m- orp-chlorophenoxy, o-, m- or p-bromophenoxy, etc.

(24) C₁₋₁₀ haloalkyl, e.g. difluoromethyl, trifluoromethyl,trifluoroethyl, trichloroethyl, etc. Furthermore, where the hydrocarbonresidue is cycloalkyl, cycloalkenyl, aryl or aralkyl, it may have 1 to 4C₁₋₄ lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,etc as substituents.

Among the exemplified hydrocarbon residues, alky, aryl and aralkylgroups are preferable. The hydrocarbon residue having 1 to 8 is alsopreferable.

The acyl group of the hydrocarbon residue represented by R¹ or R⁶includes a group having a general formula of —COR², —CONHR², —CSR² or—CSNHR² wherein R² represents hydrogen or the above exemplifiedhydrocarbon group represented by R¹ or R⁶. The hydrocarbon group of R²may have 1 to 2 substituents in substitutable position as selected fromamong the above exemplified group under (1) through (23). Among them,C₁₋₇ acyl group wherein R² is C₁₋₆ hydrocarbon group such as C₁₋₆ alkylgroup (e.g. methyl, ethyl etc.), C₂₋₆ alkenyl group (e.g. vinyl), C₂₋₆alkynyl group (e.g. ethynyl), C₃₋₆ cycloalkyl group (e.g. cyclohexyl),C₃₋₆ cycloalkenyl group (e.g. cyclohexenyl) or phenyl is preferable.

The oxycarbonyl group of the hydrocarbon residue represented by R¹ or R⁶includes a group having a general formula of —COOR² wherein R² is thesame meaning definded above. The hydrocarbon group of R² may have 1 to 2substituents in substitutable position as selected from among the aboveexemplified group under (1) through (23). Preferred, among thealkoxycarbonyl group, is the group wherein R² is C₁₋₆ hydrocarbon groupsuch as C₁₋₆ alkyl group (e.g. methyl, ethyl etc.), C₂₋₆ alkenyl gorup(e.g. vinyl), C₂₋₆ alkynyl group (e.g. ethynyl), C₃₋₆ cycloalkyl group(e.g. cyclohexyl), C₃₋₆ cycloalkenyl group (e.g. cyclohexenyl) orphenyl.

The optionally substituted heterocyclic group which may be bound througha hetero-atom includes, among others, 5- to 8-membered heterocyclicgroups or condensed heterocyclic groups derived therefrom containing 1to 4 hetero-atoms selected from among oxygen, sulfur, nitrogen and thelike in addition to at least one carbon atoms for example 5-memberedhetero-cyclic groups containing 1 to 4 hetero-atoms selected from amongoxygen, sulfur, nitrogen and the like in addition to at least one carbonatom, such as 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2,3- or4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc., 6-membered heterocyclicgroups containing 1 to 4 hetero-atoms selected from among oxygen,sulfur, nitrogen and the like in addition to at least one carbon atom,such as N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl,N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl,oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl,thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl,triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or4-pyridazinyl, etc. and bicyclic or tricyclic condensed heterocyclicgroups containing 1 to 4 hetero-atoms selected from among oxygen,sulfur, nitrogen and the like in addition to at least one carbon atom,such as benzofuryl, benzothiazolyl, benzoxazolyl,tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, benzimidazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolynyl,quinoxalinyl, indolidinyl, quinolidinyl, 1,8-naphthylidinyl, purinyl,putheridinyl, dibenzofuranyl, carbazolyl, acrylidinyl, phenanthrydinyl,chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.Among them uncondensed heterocyclic rings, especially 5- or 6-memberedrings, are preferable. Any of such heterocyclic groups may have 1 to 5substituent groups selected from among

(1) C₁₋₄ alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, ter-butyl, etc.

(2) C₂₋₄ alkenyl, e.g vinyl, 1-methylvinyl, 1-propenyl, allyl, etc.

(3) C₂₋₄ alkinyl, e.g. ethinyl, 1-propinyl, proparqyl, etc.

(4) C₃₋₆ cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.

(5) C₅₋₇ cycloalkenyl, e.g. cyclopentenyl, cyclohexenyl, etc.

(6) C₇₋₁₁ aralkyl, e.g. benzyl, α-methylbenzyl, phenethyl, etc.

(7) phenyl

(8) C₁₋₆ alkoxy, e.g. methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, etc.

(9) phenoxy

(10) C₁₋₆ alkanoyl, e.g. formyl, acetyl, propionyl, n-butyryl,iso-butyryl, etc.

(11) benzoyl

(12) C₁₋₆ alkanoyloxy, e.g. formyloxy, acetyloxy, propionyloxy,n-butyryloxy, iso-butyryloxy, etc., benzoyloxy

(13) carboxyl

(14) C₂₋₇ alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, etc.

(15) carbamoyl

(16) N-mono-C₁₋₄ alkylcarbamoyl, e.g. N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl, etc.

(17) N,N-di-C₁₋₄ alkylcarbamoyl, e.g. N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, etc.

(18) cycloaminocarbonxl, e.g. 1-aziridinylcarbonyl,1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl,N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.

(19) halogens, e.g. F, Cl, Br, I, etc.

(20) mono-, di- or tri-halo-C₁₋₄ alkyl, e.g. chloromethyl,dichloromethyl, trifluoromethyl, trifluoroethyl, etc.

(21) oxo

(22) amidino

(23) imino

(24) amino

(25) mono-C₁₋₄ alkylamino, e.g. methylamino, ethylamino, propylamino,isopropylamino, butylamino, etc.

(26) di-C₁₋₄ alkylamino, e.g. dimethylamino, diethylamino,dipropylamino, diisopropylamino, dibutylamino, etc.

(27) 3- to 6-membered cycloamino containing 1 to 3 hetero-atoms selectedfrom among oxygen, sulfur, nitrogen and the like in addition to at leastone carbon atom and one nitrogen atom, such as aziridinyl, azetidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl,imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl,N-methylpiperazinyl, N-ethylpiperazinyl, etc.

(28) C₁₋₆ alkanoylamido, e.g. formamido, acetamido, trifluoroacetamido,propionylamido, butyrylamido, iso-butyrylamido, etc.

(29) benzamido

(30) carbamoylamino

(31) N—C₁₋₄ alkylcarbamoylamino, e.g. N-methylcarbamoylamino,N-ethylcarbamoylamino, N-propylcarbamoylamino,N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.

(32) N,N-di-C₁₋₄ alkylcarbamoylamino, e.g. N,N-dimethylcarbamoylamino,N,N-diethylcarbamoylamino, N,N-dipropylcarbamoylamino,N,N-dibutylcarbamoylamino, etc.

(33) C₁₋₃ alkylenedioxy, e.g. methylenedioxy, ethylenedioxy, etc.

(34) —B(OH)₂

(35) hydroxy

(36) epoxy (—O—)

(37) nitro

(38) cyano

(39) mercapto

(40) sulfo

(41) sulfino

(42) phosphono

(43) dihydroxypolyol

(44) sulfamoyl

(45) C₁₋₆ monoalkylsulfamoyl, e.g. N-methylsulfamoyl, N-ethylsulfamoyl,N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.

(46) di-C₁₋₄ alkylsulfamoyl, e.g. N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl, etc.

(47) C₁₋₆ alkylthio, e.g. methylthio, ethylthio, propylthio,isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.

(48) phenylthio

(49) C₁₋₆ alkylsulfinyl, e.g. methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, etc.

(50) phenylsulfinyl

(51) C₁₋₆ alkylsulfonyl, e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, etc. and

(52) phenylsulfonyl.

The above optionally substituted hydrocarbon residue or heterocyclicgroup which may be bound through a hetero-atom is, for example, thenitrogen atom of amino, substituted amino (e.g. amino C₁₋₄ alkylamino,hydroxyamino, etc.), or hydrazino, the sulfur atom of thiocarbonyl orsulfino, or an oxygen atom.

Preferred, among the above-mentioned optionally substituted hydrocarbonresidues and heterocyclic groups which may be bound through ahetero-atom, are optionally substituted alkyl, aryl, aralkyl andoptionally substituted nitrogen-containing heterocyclic groups which maybe bound through a hetero-atom and more preferred are optionallysubstituted C₁₋₄ alky group. C₁₋₇ acyl group and C₁₋₇ oxycarbonyl groupare also preferable.

The group bound through a carbon, oxygen or sulfur atom, represented byR² and R³, includes, among others,

(1) cyano

(2) carboxy

(3) carbamoyl

(4) mercapto

(5) hydroxy

(6) C₁₋₄ alkyl, e.g. methyl, ethyl, propyl, iso-propyl, etc.

(7) C₁₋₆ alkylthio, e.g. methylthio, etc.

(8) C₇₋₁₁ alalkylthio, e.g. benzylthio, etc.

(9) C₂₋₄ alkenyl, e.g vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl,etc.

(10) C₂₋₄ alkinyl, e.g. ethinyl, 1-propinyl, propargyl, etc.

(11) C₁₋₆ alkoxy e.g. methoxy, etc.

(12) C₃₋₆ cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl, etc.

(13) C₆₋₁₀ aryl, e.g. phenyl, naphthyl, etc, or

(14) 5- to 7-membered heterocyclic groups containing 1 to 4 hetero-atomsselected from among nitrogen, sulfur, oxygen and the like in addition toat least one carbon atom, such as pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl,pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, dioxolanyl, piperidino,morpholino, N-methylpiperazinyl, N-ethylpiperazinyl, dioxanyl, etc.Among the above-mentioned groups, the groups mentioned under (6) through(14) may have 1 or 2 substituent groups in substitutable positions asselected from among

(a) halogens, e.g. Cl, F, etc.

(b) hydroxy

(c) oxo

(d) C₁₋₄ alkoxy, e.g. methoxy, ethoxy, etc.

(e) di-C₁₋₄ alkylamino, e.g. dimethylamino, diethylamino, etc.

(f) halo-C₁₋₄ alkyl, e.g. chloromethyl, trifluoromethyl, trifluoroethyl,etc.

(g) C₁₋₄ acyl, e.g. formyl, acetyl, etc.

(h) hydroxy-C₁₋₄ alkyl, e.g. hydroxymethyl, 2-hydroxyethyl, etc.,

(i) C₁₋₄ alkoxy-C₁₋₄ alkyl, e.g. methoxymethyl, 2-ethoxyethyl, etc.

(j) thioxo,

(k) sulfide,

(l) C₃₋₆ cyloalkyl, e.g. cyclopropyl, etc., and

(m) mercaplo

The halogen atom may for example be chlorine, bromine, fluorine oriodine.

Preferred, among the above, are halogen atoms and optionally substitutedalkyl or aryl groups which may be bound through an oxygen or sulfuratom. Among alkyl groups a low alkyl group of 1 to 4 carbon atoms ispreferable and phenyl is a preferable aryl group.

The group bound through a carbon, nitrogen, oxygen or sulfur atom, R⁴and R⁵, includes

(1) cyano

(2) carboxy

(3) carbamoyl

(4) amino

(5) nitro

(6) hydroxy

(7) mercapto

(8) C₁₋₄ alkyl, e.g. methyl, ethyl, propyl, iso-propyl, etc.

(9) C₂₋₄ alkenyl, e.g. vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl,etc.

(10) C₂₋₄ alkinyl, e.g. ethinyl, 1-propinyl, propargyl, etc.

(11) C₃₋₆ cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl, etc.

(12) C₆₋₁₀ aryl, e.g. phenyl, naphthyl, etc. or

(13) 5- to 7-membered heterocyclic groups containing 1 to 4 hetero-atomsselected from among nitrogen, sulfur, oxygen and the like in addition toat least one carbon atom, such as pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl,pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, dioxolanyl, piperidino,morpholino, N-methylpiperazinyl, N-ethylpiperazinyl, dioxanyl, etc.Among these groups, the groups mentioned under (8) through (13) may have1 or 2 substituent groups in substitutable positions as selected fromamong

(a) halogens, e.g. Cl, F, etc.

(b) hydroxy

(c) oxo

(d) C₁₋₄ alkoxy, e.g. methoxy, ethoxy, etc

(e) di-C₁₋₄ alkylamino, e.g. dimethylamino, diethylamino, etc.

(f) halo-C₁₋₄ alkyl, e.g. chloromethyl, trifluoromethyl, trifluoroethyl,etc.

(g) C₁₋₄ acyl, e.g. formyl, acetyl, etc.

(h) hydroxy-C₁₋₄ alkyl, e.g. hydroxymethyl, 2-hydroxyethyl, etc., and

(i) C₁₋₄ alkoxy-C₁₋₄ alkyl, e.g. methoxymethyl, 2-ethoxyethyl, etc.

The halogen may for example be chlorine, bromine, fluorine or iodine.

Preferred, among the above, are halogens and alkyl or aryl groupsoptionally substituted and/or each bonding through a nitrogen, oxygen orsulfur atom.

R¹ and R², or R⁵ and R⁶, may each bind together to form a chemical bond,that is to say a double bond between the carbon atom at 5-position andnitrogen atom at 4-position or between the carbon atom at 6-position andnitrogen atom at 1-position of the triazine ring. The double bondbetween 4- and 5-positions and that between 1- and 6-positions may existconcurrently but it is preferable that only one of them exists and ismore preferable that a double bond be present between the 1- and6-positions.

Where the triazine ring is tautomeric, the respective tautomers are alsosubsumed in the concept of triazine derivative of this invention.

Among the triazine derivatives of the present invention the compound ofthe following formula or salt thereof are preferable:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are the same meanings defined above,

ring B is an optionally substituted 5- or 6-membered cyclic group whichmay contains hetero atoms,

ring C is an optionally substituted phenylen group, Y is a chemicalbond, —O—, —S(O)_(m)— or an optionally protected amino or an optionallysubstituted lower hydrocarbon and

m is 0, 1 or 2.

Optionally substituted 5- or 6-membered cyclic group represented by ringB includes carbon rings such as cycloalkyl, such as cyclopentyl orcyclohexyl, etc., cycloalkenyl, such as 1-, 2- or 3- cyclopentenyl, 1-,2- or 3-cyclohexenyl, etc., phenyl or heteroaromatic groups containing 1to 4 hetero-atoms selected from among oxygen, sulfur, nitrogen and thelike in addition to at least one carbon atom, for example 2- or3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4-or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl),1,3,4-thiadiazolyl, 4- or 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc.,N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or5-pyrimidinyl, oxoimidazinyl, dioxotriazinyl, pyranyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, triazinyl, oxotriazinyl, 3-or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, etc. Amongthem, 6-membered cyclic groups, especially phenyl is preferable and6-membered nitrogen-containing heterocyclic groups are particularlydesirable when ring B is a heterocyclic group.

Such a cyclic group may be substituted, in 1 to 5 or preferably 1 to 3substitutable positions, by the following substituent groups, amongothers:

(1) C₁₋₄ alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, etc.

(2) C₁₋₄ lower alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, s-butoxy, t-butoxy, etc.

(3) carboxy

(4) carbamoyl

(5) halogens, e.g. F, Cl, Br, I, etc.

(6) mono-, di- or tri halo-C₁₋₄ alkyl e.g. chloromethyl, dichloromethyl,trifluoromethyl, trifluoroethyl, etc.

(7) amino

(8) —B(OH)₂

(9) hydroxy

(10) nitro

(11) cyano

(12) mercapto

(13) sulfo

(14) sulfino

(15) phospho and

(16) C₁₋₄ acyl e.g. folmyl acetyl etc.

Halogen atom or alkyl or haloalkyl group is preferable.

When the substitutions exist on two ring-forming atoms adjacent to eachother, they may bind together to form a ring which is condensed with thering B.

The optionally substituted phenylene group represented by the ring C maybe substituted by 1 to 4 preferably 1 to 2, substituents selected fromthose of the ring A. Among them, a halogen atom, alkyl, alkoxy orhaloalkyl group is desirable.

The lower hydrocarbon residue represented by Y includes a hydrocarbongroup of 1 to 6 carbon atoms, for example C₁₋₄ alkylene such asmethylene, ethylene, propylene, trimethylene, tetramethylene etc, C₂₋₆alkenylene such as vinylene, propenylene, 1- or 2-butenylene,butadienylene etc. or C₂₋₆ alkylydene such as ethylydene, propilydenebuthylydene etc. These lower hydrocarbon groups are substituted with 1to 4 substituents selected from

(1) halogens, e.g. Cl, F, etc.

(2) hydroxy,

(3) oxo,

(4) cyano,

(5) C₁₋₄ alkoxy, e.g. methoxy, ethoxy, etc.

(6) mono- or di-C₁₋₄ alkylamino, e.g. methylamino, ethyklamino,propylamino, dimethylamino, diethylamino, dipropylamino, etc.

(7) halo-C₁₋₄ alkyl, e.g. fluoromethyl, fluoethyl, chloromethyl,chloroethyl, bromomethyl, bromoethyl, trifluoromethyl, trifluoroethyl,chloropropyl, etc.

(8) C₁₋₄ acyl, e.g. formyl, acetyl, propyonyl, etc.

(9) hydroxy-C₁₋₄ alkyl, e.g. hydroxymethyl, hydroxyethyl,2-hydroxyethyl, hydroxypropyl, etc.

(10) C₁₋₄ alkoxy-C₁₋₄ alkyl, e.g. methoxymethyl, 2-ethoxyethyl, etc.

(11) C₁₋₄ alkoxy-carbonyl, e.g. methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl etc.

(12) thioxo and

(13) C₁₋₄ alkylthio, e.g. methylthio, ethylthio, propylthio,isopropylthio, buthylthio, isobuthylthio, sec-buthylthio,tert-buthylthio etc. and so on.

Among them, a hydrocarbon group having 1 to 2 carbon atom in a straightchain which links the rings B and C such as optionally substitutedmethylene, ethylene, vinylene and ethynylene is preferable. Further, aC₁₋₃ alkylene, C₂₋₄ alkylene or C₂₋₄ alkenylidene group which mayoptionally be substituted with 1 to 2 of the above mentionedsubstituents is most preferable.

For example, such a preferable embodiment includes methylene groupoptionally substituted with chloro, fluoro, methyl, monofluoromethyl,monochloromethyl, trifluoromethyl, hydroxy, carboxy, oxo (to a carbonylgroup), thioxo (to a thiocarbonyl group), methoxycarbonyl,ethoxycarbonyl, cyano or the like, ethylene group optionallysubstituted, at position 1 or 2 independently, with chloro, fluoro,methyl, monofluoromethyl, monochloromethyl, trifluoromethyl, hydroxy,carboxy, cyano or like, propylen group optionally substituted, atposition 1, 2, or 3 independently, with chloro, fluoro, methyl,monofluoromethyl, monochloromethyl, trifluoromethyl, hydroxy carboxy,oxo (to form e.g. ethylidenecarbonyl, acetylethylene etc.), methoxy,ethoxy, methylthio, ethylthio, dimethylamino, diethylamino or the like,C₂₋₄ alkenylen group optionally substituted with chloro, fluoro methyl,monofluoromethyl, monochloromethyl, hydroxy, carboxy, cyano or the likeindependently on any substituted position, and C₂₋₄ alkylidene groupoptionally substituted with chloro, fluoro, oxo (to form e.g.formylmethylene, acetylmethylene, methylcarbonylmethylene etc, hydroxy,methoxy, ethoxy, methylthio, dimethylamino, diethylamino or the like.

In the optionally protected the amino of Y, amino group may be protectedwith a group selected from

(1) formyl

(2) C₁₋₆ alkyl-carbonyl, e.g. acetyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl which may substituted with halogen atoms, e.g. Cl, Br, Fetc.

(3) C₆₋₁₀ aryl-carbonyl, e.g. phenylcarbonyl which may substituted with1 to 3 halogen atom, e.g. Cl, Br, F etc, C₁₋₆ alkylcarbonyl, e.g.methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl etc. ornitro group

(4) C₁₋₆ alkyloxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl whichmay substituted with 1 to 3 halogen atom, e.g. Cl, Br, F etc, C₁₋₆alkylcarbonyl, e.g. methylcarbonyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl etc. or nitro group

(5) C₆₋₁₀ aryloxycarbony, e.g. phenoxycarbony which may substituted with1 to 3 halogen atom, e.g. Cl, Br, F etc, C₁₋₆ alkylcarbonyl, e.g.methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl etc. ornitro group

(6) C₇₋₁₂ aralkyl-carbonyl, e.g. benzylcarbonyl, phenylethylcarbonylwhich may substituted with 1 to 3 halogen atoms e.g. Cl, Br, F etc, C₁₋₆alkylcarbonyl, e.g. methylcarbonyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl etc. or nitro group

(7) trityl which may substituted with 1 to 3 halogen atom, e.g. Cl, Br,F etc, C₁₋₆ alkylcarbonyl, e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, butylcarbonyl etc. or nitro group and

(8) phthaloyl which may substituted with 1 to 3 halogen atom, e.g. Cl,Br, F etc, C₁₋₆ alkylcarbonyl, e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, butylcarbonyl etc. or nitro group or the like. However,any group may be used as long as it can be re-converted to aminochemically in the synthesis rout using a general technique of organicchemistry or under physiological conditions (for example by enzymaticlysis or metabolism).

Among the divalent groups represented by Y, —O—, —S— or optionallysubstituted C₁₋₆ bivalent hydrocarbon group, especially optionallysubstituted C₁₋₄ alkylen or C₂₋₄ alkylydene group is preferable.

In the above formula, prefered embodiments of R¹ and R⁶ are eachhydrogen atom or an optionally substituted hydrocarbon residue;especially alkyl, aryl or aralkyl group, which may be bound through ahetero atom.

Further, hydrogen, C₁₋₇ acyl group (e.g. acetyl, benzyl etc.), C₁₋₇oxycarbonyl group (e.g. methoxycarbonyl, hydroxy carbonyl etc.) or anoptionally substituted alkyl such as C₁₋₄ alkyl, mono-, di- ortrihalo-C₁₋₄ alkyl, C₁₋₄ alkylcarbonyl or the like is more preferred asR¹.

In the above formula, R² and R³ are preferably selected each from amonghydrogen atom, halogen atom and-an optionally substituted alkyl such asC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, mono-, di- or trihalo-C₁₋₄ orlike, aryl such as phenyl, phenoxy, phenylthio, mono-, di- ortri-halophenyl or aralkyl group such as benzyl, benzylthio or the like,or may be taken together to form ═S, more preferably selected each fromamong hydrogen atom, halogen atom and an optionally substituted alkylgroup. Further, at least either, especially both of R² and R³ maypreferably be a hydrogen atom.

In the above formula, R⁴ and R⁵ are preferably selected each from among,hydrogen atom, halogen atom and an optionally substituted alkyl or arylgroup, more preferably selected from hydrogen or an optionallysubstituted C₁₋₄ alkyl group. Further, at least either, especially both,of R⁴ and R⁵ may preferably be a hydrogen atom.

R⁶ are preferred to be hydrogen or an optionally substituted C₁₋₄ alkylgroup such as C₁₋₄ alkyl, mono-, di- or trihalo-C₁₋₄ alkyl, C₁₋₄ acyl,C₁₋₄ alkylcarbony or the like.

The compounds in which R¹ and R² and/or R⁵ and R⁶ bind together to forma chemical bond are also desired.

The salt of a triazine derivative according to this invention ispreferably a salt physiologically acceptable for animals and as suchincludes salts with alkali metals such as sodium, potassium, etc., saltswith alkaline earth metals such as calcium etc., salts with inorganicacids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoricacid, etc., and salts with organic acids such as acetic acid, succinicacid and so on.

The triazine derivative of this first embodiment can be produced by,inter alia, the following reaction routes.

Reaction a)

wherein ring A, X, R¹, R², R³, R⁴, R⁵ and R⁶ have the meanings definedhereinbefore; L represents hydrogen or an alkyl or aryl group.

The above reaction a) is directed to cyclization of hydrazine derivative(2) to a compound of general formula (1).

This reaction is generally conducted in an inert solvent or in theabsence of a solvent, optionally in the presence of a Lewis acid or aLewis base. The reaction temperature is generally about 60 to about 200°C. and preferably about 100 to about 160° C. For this reaction,virtually any inert organic solvent can be employed. Thus, it may can beany of the reaction solvents which are generally used in organicchemistry, for example, benzene, ligroin, benzine, toluene, xylene,methylene chloride, ethylene chloride, chloroform, carbon tetrachloride,dichloroethane, chlorobenzene, o-dichlorobenzene, ethers (e.g. dibutylether, glycol dimethyl ether, diglycol dimethyl ether, tetrahydrofuran,dioxane, etc.), ketones (e.g. methyl ethyl ketone, methyl isopropylketone, methyl isobutyl ketone, etc.), esters (e.g. ethyl acetate etc.),nitriles (e.g. acetonitrile, propionitrile, etc.), amides (e.g.dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide,etc.), N-methylpyrrolidone, dimethylsulfoxide, tetramethylenesulfone,mercaptoacetic acid, pyridine, and so on. This reaction may be carriedout while the byproduct such as alcohol or water is removed.

Reaction b)

wherein ring A, R¹-R⁴, L and X have the meanings defined hereinbefore.

The above reaction b) comprises reacting hydrazine (3) with a carbomicacid derivative (4) to give a hydrozone derivative (2a) followed byreduction to provide a hydrazine derivative (2).

The compound (2a) obtained by reacting compound (3) with compound (4) inan inert organic solvent is then reduced in the conventional manner. Theinert organic solvent that can be used includes, among others,hydrocarbons (e.g. nonane, decane, dodecane, xylene, toluene, benzene,etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane,carbone tetrachloride, chlorobenzene, dichloroethane, etc.), alcohols(e.g. diethylene glycol etc.), ethers (e.g. diethylene glycol monobutylether, diethylene glycol dibutyl ether, etc.), dioxane, tetrahydrofuran,dimethylformamide, sulfoxides and sulfones such as di-methyl sulfoxide,tetramethylenesulfone and so on. This reaction can also be conducted inthe presence of a Lewis acid or a dehydrating agent (e.g.dicyclohexylcarbodiimide, carbonyidiimidazole, etc.).

This reaction can be carried out generally at a temperature within therange of about −10° C. to about 150° C. In particular, the temperaturerange of about 10 to about 20° C. is preferred when a dehydrating agentis used and the range of about 60 to about 110° C. is preferred in otherinstances.

Reduction of compound (2a) can be achieved by treating (2a) in thepresence of about 1 to about 10 equivalents of a catalyst (palladium,NaBH₄, LiAlH₄, etc.) in alcohol or water at about 25 to about 60° C. forabout 0.5 to about 10 hours.

The compound (4) can be synthesized by the method of Tamejiro Hiyama etal. [Bull. Chem, Soc. Japan., 45, 1863-1866 (1972)].

Reaction c)

wherein ring A, R¹, R², R³, R⁴, L and X have the same meanings definedhereinbefore; R⁷ represents an optionally protected amino.

The above reaction c) is directed to cyclization of semicarbazonederivative (5) to synthesize a compound of the first embodiment. Thecyclization reaction is carried out in an inert solvent or in theabsence of a solvent, optionally in the presence of a Lewis acid or aLewis base. The reaction is generally conducted at a temperature withinthe range from about 0° C. to about 200° C. In particular, the reactiontemperature of about 5 to about 30° C. is preferred when ahydroxyl-activating agent (e.g. trifluoroacetic anhydride, aceticanhydride, phosphorus oxychloride, etc.) is employed. Where nohydroxyl-activating agent is employed, the reaction is carried out atabout 100 to about 200° C., preferably at about 140 to about 180° C. Asthe reaction solvent, virtually any inert organic solvent can beemployed. Thus, such solvent includes aliphatic and aromatichydrocarbons (e.g. benzene, ligroin, benzine, toluene, xylene, etc.),halogenated hydrocarbons (e.g. methylene chloride, ethylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,o-dichlorobenzene, etc.), ethers (e.g. dibutyl ether, glycol dimethylether, diglycol dimethyl ether, tetrahydrofuran, dioxane, etc.), ketones(e.g. methyl ethyl ketone, methyl isopropyl ketone, methyl isobutylketone, etc.), esters (e.g. ethyl acetate etc.), nitriles (e.g.acetonitrile, propionitrile, etc.), amides (e.g. dimethylformamide,dimethylacetamide, hexamethylphosphoric triamide, etc.),N-methyl-pyrrolidone, dimethyl sulfoxide, tetramethylenesulfone,mercaptoacetic acid, pyridine, etc. To remove the residualhydroxyl-activating agent after the reaction, an organic base such aspyridine, triethylamine, dimethylpyridine, etc. or an inorganic basesuch as potassium hydroxide, sodium hydroxide, etc. can be employed.

This reaction may be conducted in the presence of a dehydrating agent,such as dicyclohexylcarbodiimide, carbonyldiimidazole and so on.

The tetrahydrotriazine compound (1a) thus obtained can be reduced in themanner described for reaction b) to give the hexahydrotriazine compound(1b).

Furthermore, when the 3,3-disubstituted semicarbazide derivative (6) isused as an intermediate, it can be heat-cyclized in the same manner asthe compound (5) to synthesize the-tetrahydrotriazine compound (1a). Thecyclization reaction is carried out generally at a temperature of about60 to about 160° C., preferably about 80 to about 120° C. This reactioncan also be conducted with the aid of a catalyst, that is to say in thepresence of a Lewis acid or the like (e.g. trifluoroborane etherate,methanesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid,polyphosphoric acid, etc.). In this reaction, the protection group forthe optionally protected amino represented by R⁷ is any group generallyused in organic chemistry [c.f. Shinjikken Kagaku koza Vol. 14, p.2555Edit. Nihon seikagakkai].

The compound (6), wherein R⁷ is amino, can be obtained by a processwhich comprises dissolving anN-alkyl-N-(2,2-dialkoxyethyl)-N′-phenylurea in an aprotic solvent (e.g.dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.),adding a finely divided (ca. 50-100 μm) powder of potassium hydroxide orsodium hydroxide, then adding an aminating agent (e.g.hydroxyamino-O-sulfonic acid, 3-chloro-2-cyanopherethoxy amine, etc.) ina few portions under vigorous stirring at about 0 to about 10° C.,further stirring the reaction mixture at about 25 to about 30° C. foranother 2 hours, pouring it in iced water, neutralizing the mixture withdiluted hydrochloric acid, and extracting it with chloroform.

The N-alkyl-N-(2,2-dialkoxyethyl)-N′-phenylurea can be synthesized bythe conventional reaction between phenyl isocyanate andN-2,2-dialkoxyethylamine.

The compound (6) in which R⁷ is a protected amino can be obtained byfollowing reaction (c).

Reaction d)

wherein A, R¹, R², R³, R⁴, R⁷, L and X have the same meanings definedhereinbefore; R⁸ is halogen atom or an optionally substituted C₁₋₄alkoxy (e.g. halo C₁₋₄ alkyl etc.) or phenoxy and Z is halogen atom.

The above reaction (d) is directed to an amination followed by anacylation of a hydrazine derivative in the presence of base to providecompound (6). The reaction is generally conducted at a temperature within the range of about −5 to about 40° C., preferably about 5 to about10° C. The base used therein includes an organic base such as pyridine,triethylamine, DBU, collidine, 1,1,3,3-tetramethylguanizine and so on.

As the reaction solvent, virtually any inert organic solvent can beemployed. Thus, such solvent includes aliphatic and aromatichydrocarbons (e.g. benzene, ligroin, benzine, toluene, xylene, etc.),halogenated hydrocarbons (e.g. methylene chloride, ethylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,o-dichlorobenzene, etc.), ethers (e.g. dibutyl ether, glycol dimethylether, diglycol dimethyl ether, tetrahydrofuran, dioxane, etc.), ketones(e.g. methyl ethyl ketone, methyl isopropyl ketone, methyl isobutylketone, etc.), esters (e.g. ethyl acetate etc.), nitriles (e.g.acetonitrile, propionitrile, etc.), amides (e.g. dimethylformamide,dimethylacetamide, hexamethylphosphoric triamide, etc.),N-methyl-pyrrolidone, dimethyl sulfoxide, tetramethylenesulfone,mercaptoacetic acid, pyridine, etc.

Of the compounds of this invention, species in which position-5represents ═S can be obtained by a process which comprises heating a1,2,4-triazine-1,3-dione compound (which can be synthesized inaccordance with the manner reported by Max W. Miller et al., J. Med.Chem., 22, 1483, 1979) with Lawesson's reagent or phosphoruspentasulfide in a solvent such as aliphatic or aromatic hydrocarbonswhich may optionally be substituted (e.g. benzene, ligroin, benzine,toluene, xylene, methylene chloride, ethylene chloride, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene,etc.), ethers (e.g. dibutyl ether, glycol dimethyl ether, diglycoldimethyl ether, tetrahydrofuran, dioxane, etc.), and ketones (e.g.methyl ethyl ketone etc.). The thus-synthesized 5-thion (═S) compoundcan be reduced with the aid of Raney nickel to give the 5-methylenecompound.

The compound (1) and physiologically acceptable salt of the firstembodiment are suitable for the control of parasitic protozoaencountered in the husbandry and/or production of animals such asmammals, birds, fish or insects and show activity against individual orall stages of growth of such pathogenic parasitic protozoa. Furthermore,these compounds show sufficiently effective activity within the usualrange of doses against the protozoa which are resistant to the knowndrugs. As a result, morbidity and the mortality of host animals aredecreased and, hence, the efficiency of animal production andreproduction (e.g. the efficiency of production of meat, milk, furs,hides and skins, eggs, honey, etc. as well as the efficiency ofbreeding) are increased. Moreover, use of the compound of the firstembodiment enables economical raising of various animals with goodefficiency by preventing protozoal infection such as coccidialinfection.

The protozoan diseases that can be controlled by the compound of thisfirst embodiment are of a broad range Thus, the parasitic protozoa thatcan be controlled include, among others, protozoa of the Apicomplexa,particularly of the family Eimeriidae, such as the genus Eimeria, e.g.E. acervulina, E. adenoides, E. alabamensis, E. arloingi, E.auburnensis, E. bovis, E. brunetti, E. canis, E. contorta, E.ellipsoidalis, E. falciformis, E. gallopavonis, E. hagani, E.intestinalis, E. magna, E. maxima, E. meleagridis, E. meleagrimitis, E.mitis, E. mivati, E. necatrix, E. ninakohlyakimovae. E. ovis, E. parva,E. pavonis, E. perforans, E. piriformis, E. praecox, E. stiedai, E.suis, E. tenella, E. truncata, E. zuernii, etc., the genus Isospora suchas I. belli, I. canis, I. felis, I. rivolta, I. suis, etc., Toxoplasmagondii, and the genus Crytosporidium, particularly Cryptosporidium s.p.,the family Sarcocystidae, e.g. S. bovicanis, S. bovihominis, S.ovicanis, S. ovifelis, S. suihominis, etc., the genus Leucocytozoon,e.g. L. simondi, L. caulleryi, etc., the family Plasmodiidae, e.g. P.berghei, P. falciparum, P. malariae, P. ovale, P. vivax, etc., protozoaof the subclass Piroplasmea, more specifically of the genus Babesia,e.g. B. argentina, B. bovis, B. canis, etc., the genus Theileria, e.g.T. parva etc., Adeleina, Hepatozoon canis and so on.

Furthermore, protozoa taxonomically belonging to Myxospora orMicrospora, protozoa of the genus Glugea and those of the genus Nosemamay also be mentioned.

The compound (1) and its physiologically acceptable salt can be usedboth prophylactically and therapeutically in protozoan infections inmammalian animals (e.g. cattle, horse, swine, sheep, goat, camel,buffalo, donkey, rabbit, deer, reindeer, mink, chinchilla, raccoon,mouse, rat, guinea pig, golden hamster, dog, cat, etc.), birds (e.g.chicken, quail, goose, turkey, duck, wild duck, dove, pigeon, etc.),fresh-water and sea-water fishes (e.g. carp, eel, trout, smelt fish,salmon, ruffer, sole, flatfish, sea-bream, sea bass, catfish, etc.) andeven in insects such as honey bees.

The compound (1) and its physiologically acceptable salt can be safelyadministered to any of the above-mentioned animals, either as they areor in various dosage forms according to the route of administrationwhich may be oral or parenteral. The dosage forms mentioned above can bemanufactured by the per se known methods (e.g. Japanese patentapplication unexamined publication No. HS-1047 which corresponds toEP-A-476439, Japanese patent application unexamined publication No.H5-117250 which corresponds to EP-A-457015, Japanese patent applicationunexamined publication No. H2-240003 which corresponds to EP-A-383285,Japanese patent application unexamined publication No. S62-61972 whichcorresponds to EP-A-215354, etc.).

The compound of the general formula (1) or physiologically acceptablesalt thereof in the first embodiment can be used for preparing aprophylactic and therapeutic agent for protozoal disease by mixing themwith a pharmaceutically acceptable additive(s) such as a diluent and anexcipient, if necessary, to formulate the antiprotozoal compositionaccording to a known pharmaceutical method, and then incorporated infeed or drinking water for administration.

The antiprotozoal agent of the first embodiment is prepared, forexample, by diluting a compound of the general formula (1) or itsphysiologically acceptable salt, independently or in a mixed state, witha solid or liquid carrier, by undiluting them, or by stabilizing them bycoating and the like to formulate powders, dusts, granules, tablets,solutions, emulsions, pastes, capsules, premixed, injections and thelike. The antiprotozal agent of the first embodiment is also prepared bydispersing directly the compound of the general formula (1) or itsphysiologically acceptable salt in feed, drink and the like, or byincorporating therein after dispersed in a carrier. The carrier may beany one, as long as it is physiologically harmless per se. The carrierswhich function as feed or a component of feed are preferable. The solidcarriers include, for example, lactose, sucrose, starch, wheat meal,corn meal, wheat bran, soybean cake, extracted rice bran, rape seedcake, soybean crude meal, cellulose yeast, fish meal, peanut meal, shellpowder and calcium carbonate. Examples of the liquid carriers includewater, physiological saline and physiologically acceptable organicsolvents. In addition, other suitable adjuvants such as emulsifiers,dispersants, suspension aids, wetting agents, thickening agents, gelforming agents and solubilizers may be added in suitable amounts. Theremay be further incorporated preservatives, fungicides, colorants,aromatics, antibacterial agents, antibiotics, enzyme preparations,lactobacillus preparations, antifebriles, analgesics, antiphlogisticsand so on, and other agents for protozoal disease may also be compoundedin combination as long as they are different from the compound of thefirst embodiment in mechanism of action. Furthermore, various vitamins,minerals and amino acids may be incorporated.

The antiprotozoal agents of the first embodiment are administered toanimals such as mammals, birds, fish or insects, for the purpose ofprophylaxis or/and treating protozoal disease. Since in the live-stockindustry, domestic animals are usually bred or farmed in groups, it isalso included in the scope of this agents of the first embodiment toinfected individuals isolated from the group or to the whole of thegroup through feed, drinking water and the like, when it has benconfirmed that some animals in the group are attacked with protozoaldisease.

The antiprotozoal composition of this first embodiment may contain oneor more species of the compound or salt of this first embodiment.Furthermore, the composition may contain other drugs for improving thegeneral condition of animals or drugs for prophylaxis or therapy of theindicated disease. It can be used in combination with such drugs unlessadverse interactions or dilution of efficacy is foreseen.

The antiprotozoal composition of this first embodiment should containcompound (I) or a physiologically acceptable salt thereof in aconcentration of about 0.01 ppm to about 1%, preferably about 0.1 ppm toabout 0.1%. In the case of a preparation for extemporaneous dilution, itis prepared so as to contain the active drug in a concentration of about0.01 to about 90% or, preferably, about 0.1 to about 30%.

Generally, the antiprotozoal composition of this first embodiment can beadministered in a daily dose of about 0.01 to about 50 mg/kg bodyweight, preferably about 0.1 to about 5 mg/kg body weight, as compound(I) of a salt. By way of illustration, the antiprotozoal composition ofthis first embodiment can be admixed into the animal ration or diet atthe level of, as compound (I) or a salt thereof, about 0.01 to about 100ppm, preferably about 0.1 to about 50 ppm. The resulting ration can beused for both therapeutic and prophylactic purposes. Such a ration canbe generally prepared by manufacturing a concentrate or premixcontaining about 0.5 to about 30 weight %, preferably about 1 to about20 weight %, of compound (I) or salt with a feed excipient and blendingit with a regular feed. The excipient mentioned just above may forexample be a corn meal or corn-soya meal containing a small quantity ofsome dust-preventive edible oil such as corn oil or soybean oil or amineral salt. The resulting premix is evenly admixed into a regularanimal diet for administration.

For the treatment or prevention of coccidiosis in poultry, particularlyin chickens, quails, ducks, wild ducks, geese, and turkeys, generallyabout 0.01 to about 100 ppm, preferably about 0.1 to about 50 ppm, ofcompound (I) or salt is administered as previously mixed with suitableedible materials such as nutrient feeds. The drug can be added todrinking water for ingestion.

For the treatment of animals, e.g. for the therapy of coccidiosis ortoxoplasmosis, compound (I) or a physiologically acceptable salt thereofis administered in a daily dose of about 0.5 to about 100 mg/kg bodyweight. Depending on the body weight of animals, therapeutic regimen,species or breeds of animals, individual responses to the antiprotozoaldrug, dosage form or formulation, timing and intervals ofadministration, etc., it may at times be necessary to depart from theabove-mentioned dosage range. Thus, a reduced dose may prove effectivein some cases, while an increased dose may be necessary in other cases.For massive administration, the daily dosage may be advantageouslyadministered in divided doses.

The treatment of fish is carried out by the oral route, such as throughfeed, or by the short-time “drug bath” method which comprisestransferring the fish from the farming-pond to a tank filled with drugsolution (drug bath) and keeping them therein for a predetermined time(ranging from a few minutes to several hours).

However, a temporary or permanent treatment of the whole habitat (forexample a pool, aquarium, tank or pond) can also be instituted.

In such cases, compound (I) or a physiologically acceptable salt isapplied in a form suited to the particular situation. The concentrationof the antiprotozoal agent of this invention may range from about 1 ppmto about 10 weight per volume %.

For the “drug bath” treatment or the omnibus habitat treatment (pooltreatment) of fish, it is preferable to employ a solution of theantiprotozoal drug of first embodiment in a polar solvent or solventmixture which can be diluted or suspended with water.

To prepare such a solution, compound (1) or a physiologically acceptablesalt is dissolved or suspended in a polar water-soluble vehicle. It ispreferable that after addition of the compound (1) or/andphysiologically acceptable salt the vehicle shows a pH range of 7 to 10,especially about 8 to 10.

Since administration of the compound first embodiment controls parasiticprotozoan to thereby decrease the incidence of the associated diseasesand death and improve the growth retardation and deteriorated generalcondition, the first embodiment is useful for preventing the decrease ofyields in the production of meat, milk, furs, eggs, honey and so on.Moreover, the first embodiment also contributes remarkably to a safehusbandry of ornamental animals and pets.

The following examples, test examples and formulation examples areintended to describe this first embodiment in further detail and shouldby no means be construed as defining the scope of the first embodiment.The chemical structure of the compound obtained in the followingExamples are shown in the Table 3.

TEST EXAMPLE 1 Effect on Biological Test (1)

The anticoccidal affect of the compound of this first embodiment wasevaluated in chickens. Using 9-day-old male white Leghorn chicks ingroups of 3, the animals in all groups except the non-infected,untreated control group were orally inoculated with 5×10⁴ sporulatedoocysts/bird of the laboratory standard strain of Eimeria tenella. Asthe drug, a dried, crushed batch of the compound of this firstembodiment was admixed with 31.3 ppm of the standard basal ration (SDLNo. 1; Nippon Haigo Shiryo Co., Ltd.) and the chicks were allowed freeaccess to the resulting diet for 9 consecutive days beginning 24 hoursbefore the infection until day 8 after the infection. During the feedingperiod, the body weight gain of each check was determined. Furthermore,the number of bloody droppings was counted and the count of excretedoocysts was taken to evaluate the anticoccidial effect of the drug. Theresults are shown in Table 1. In the table, Compound No. corresponds tothe Compound No. in Table 3.

TABLE 1 Relative Number of body weight bloody OPG³⁾ Compound No. gain(%)¹⁾ droppings²⁾ (log) Non-infected/ 100 0   ND⁴⁾ treatment groupInfected/untreated 40.2 3.0 5.2 control group  1 100 0 ND  2 102.9 1.25ND  3 96.1 0 ND  4 91 0 ND  5 100 0 ND  6 100 0 ND  7 104.4 0 ND 15 1000 ND 22 111.9 0 ND 38 100 0 ND 39 100 0 ND 40 100 0 ND 43 100 0 ND 44100 0 ND 45 104.6 0 ND${\quad^{1)}{Relative}\quad {body}\quad {weight}\quad {gain}} = {\frac{\text{Average~~body~~weight~~gain}{{in}\quad {treatment}\quad {group}}}{\begin{matrix}{{Average}\quad {body}\quad {weight}\quad {gain}\quad {in}} \\{{non}\text{-}{infected}\quad {control}\quad {group}}\end{matrix}} \times \quad 100}$

²⁾Number of bloody droppings: The number of blood droppings per bird asdetected on the paper set under the floor-net on the peak day ofexcretion from the intestine of the chick. ³⁾OPG: The number of oocystsexcreted in 1 gram of feces (on day 7 after infection) ⁴⁾ND: Notdetected.

It is apparent from the data in Table 1 that compared with the infectedgroup, the groups treated with the compound of this invention invariablyshowed a relative body weight gain, indicating that the compound of thisfirst embodiment has excellent anticoccidial activity.

TEST EXAMPLE 2 Effect on the Biological Test (2)

The anticoccidal effect of the compound of the invention was evaluatedfollowing the method in the Test Example 1 by administration of thestandard ration containing 4 ppm of the compound. The results are shownin Table 2.

TABLE 2 Relative Number of body weight bloody OPG Compound No. gain (%)droppings) (log) Non-infected/ 100 0 ND treatment groupInfected/untreated 40.2 3.0 5.2 control group 53 92.3 0 ND 54 90.7 0 ND55 92.2 0 ND 56 95.7 0 ND 57 95.8 0 ND 58 95.7 0 ND 59 92.2 0 ND 60 90.30 ND 61 90.3 0.7 ND 62 94.5 0 ND 65 90.0 0 ND 66 98.4 0 ND 67 92.6 0 ND68 97.0 0 ND 69 94.1 0.2 ND

REFERENCE EXAMPLE 1 3,5-dichloro-4-(4′-chloro-1-methoxycarbonyl)benzylnitrobenzene

In 100 ml acetonitrile was dissolved 4.00 g p-chlorophenyl acetate, 4.54g 3,4,5-trichloronitrobenzen and 2.60 g 1,1,3,3-tetramethyl guanidinefollowed by refluxtion for 8 hours and concentrated to dryness. Theresidue was dissolved with 100 ml toluene, washed with 100 ml iced waterand 100 ml cold water, dried over MgSO₄ and concentrated. After theconcentrate was added ethanol, 6.82 g of the title compound wasfiltlated as crystals. m.p. 92-93° C.

REFERENCE EXAMPLE 23,5-dichloro-4-(4′-chloro-methoxycarbonyl)benzylaniline

In 50 ml of ethanol was dissolved 6.00 g3,5-dichloro-4-(4′-chloro-methoxycarbonyl)benzylnitrobenzen preparedaccording to Reference Example 1 followed by addition of 5-fold molarSnCl₂ and refluxed for 2 hours after the reaction solution wasconcentrated, powdered in 1 l iced water and extracted with 100 ml ofethyl acetate, after the solution was made to be alkaline by adding 10%NaOH. The extract was washed with water, dried over MgSO₄ andrecrystalized with ethanol to provide 5.12 g of the title compound. m.p.151-152° C.

REFERENCE EXAMPLE 33,5-dichloro-4-(4′-chloro-1-methoxycarbonyl)benzylphenylhydrazine

In the mixture of 100 ml of acetic acid and 30 ml of hydrochloride wasdissolved 5.00 g of3,5-dichloro-4-(4′-chloro-1-methoxycarbonyl)benzylaniline preparedaccording to Reference Example 2 followed by addition of 10 ml of 2-foldmolar sodium nitrate solution dropwise with stirring at 5-10° C.

After completion of the addition, the solution was reacted at 10-20° C.for 2 hours and further reacted at 10-20° C. for 2 hours after additionof 5-fold molar SnCl₂ dissolved in 50 ml hydrochloride dropwise withstirring at 5-10° C. The crystals thus obtained was suspended in icedwater and extracted with ethyl acetate. The extract was dried overMgSO₄, concentrated and recrystalized to give 4.20 g of the titlecompound. m.p. 113-114° C.

REFERENCE EXAMPLE 44-(4′-chloro-1-methoxycarbonyl)benzyl-3-trifluoromethyl aniline

Starting with4-(4′-chloro-1-methoxycarbonyl)benzyl-3-trifluoromethylnitrobenzene, thetitle compound was synthesized in otherwise a similar manner asReference Example 2. m.p. 103-104° C.

REFERENCE EXAMPLE 54-(4′-chloro-1-methoxycarbonyl)benzyl-3-trifluoromethylphenyl hydrazine

Starting with4-(4′-chloro-1-methoxycarbonyl)benzyl-3-trifluoromethylaniline preparedaccording to Reference Example 4, in otherwise a similar manner asReference Example 3. m.p. 95-97° C.

EXAMPLE 12-(3,5-Dichlorophenyl)-5-methoxy-2,3-dihydro-1,2,4-triazin-3-one(Compound No. 16)

In THF was dissolved 2.77 g of2-(3,5-dichloro-phenyl)-5-chloro-2,3-dihydro-1,2,4-triazin-3-onefollowed by addition of sodium methoxide in an equimolar amount to thestarting compound, and the mixture was stirred at room temperature for 1hour. After completion of this reaction, the reaction mixture wasconcentrated under reduced pressure and ice-water was added to theresidue. The resulting crystals were collected by filtration, dried anddissolved in 100 ml of chloroform. The chloroform solution was driedover anhydrous magnesium sulfate, concentrated and purified by columnchromatography (Merck Silica Gel 60; dichloromethane-methanol=10:1) toprovide 0.4 g of white crystals (m.p. 164° C.).

Elemental analysis for C₁₀H₇Cl₂N₃O₂

C H N Calcd.: 44.14; 2.59; 15.44 Found: 43.92; 2.61; 15.31

NMR [CDCl₁]δ: 4.09 (s, 3H), 7.25-7.48 (m, 1H), 7.51-7.75 (m, 2H).

EXAMPLE 22-[3,5-Dichloro-4-(4′-chloro-1-cyanobenzyl)phenyl]hexahydra-1,2,4-triazin-3-one(Compound No. 38)

To 50 ml of dichloromethane was added 2.07 g of2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)phenyl]-1-(2-hydroxyethyl)semicarbazideas well as 2-fold molar of pyridine. The solution was cooled to 0 to 5°C. and equimolar of trifluoroacetic anhydride was added dropwise withconstant stirring. After completion of the dropwise addition, thereaction was further carried out under the same conditions for one hour.The dichloromethane was then removed by concentration and 50 ml of1,4-dioxane was added to the concentrate. The mixture was refluxed for 4hours, after which the solvent was distilled off and the residue wasdissolved in chloroform. The chloroform solution was washed with icedwater, dried over anhydrous magnesium sulfate and concentrated. Thisresidue was further purified by column chromatography (Merck Silica Gel60; chloroform) to provide 0.1 g of the title compound as a whitesubstance melting at 138-139° C. (dec.).

Elemental analysis for C₁₇H₁₃Cl₃N₄O

C H N Calcd.: 51.60; 3.31; 14.16 Found: 51.53; 3.36; 14.14

NMR [CDCl₃] 67 : 3.00-3.64 (m, 4H), 4.19 (t, J=6 Hz, 1H), 5.69 (br, 1H),6.09 (s, 1H), 7.29 (s, 4H), 7.92 (s, 2H).

EXAMPLE 32-[3,5-Dichloro-4-(4′-chloro-1-cyanobenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(Compound No. 41)

Starting with 2.00 g of2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)phenyl]-1-(2-hydroxymethylmethylidenesemicarbazone, 0.38 g of the white title compound was synthesized inotherwise the same manner as Example 2. m.p. 166-167° C. Elementalanalysis for C₁₇H₁₁Cl₃N₄O

C H N Calcd.: 51.86; 2.82; 14.23 Found: 51.60; 2.87; 13.93

NMR [CDCl₃] δ: 4.00-4.20 (m, 2H), 6.14 (s, 1H), 6.45 (br, 1H), 7.15 (br,1H), 7.30 (s, 4H), 7.72 (s, 2H).

EXAMPLE 42-[3,5-Dichloro-4-(4-chloro-1′-cyanobenzyl)phenyl]-4-methylhexahydro-1,2,4-triazin-3-one(Compound No. 40)

In 50 ml of dimethylformamide was dissolved 1.18 g of1-methyl-1-(2,2-diethoxyethyl)-2-[3,5-dichlora-4-(4′-chloro-1-cyanobenzyl)phenyl]semicarbazideand the reaction was carried out at 140-145° C. with stirring for 2hours. The reaction mixture was then poured in 300 ml of iced water andextracted with 200 ml of chloroform. The extract was dried overanhydrous magnesium sulfate, concentrated to dryness. The residue wasreducted with LiAlH₄ in THF and purified by column chromatography (MerckSilica Gel 60; chloroform) to provide 0.1 g of the title compound. m.p.137-138° C.

Elemental analysis for C₁₈H₁₅Cl₃N₄O

C H N Calcd.: 52.77; 3.69; 13.68 Found: 52.74; 3.62; 13.68

NMR [CDCl₃] δ: 3.00 (s, 3H), 3.20-3.60 (m, 4H), 4.25 (br, 1H), 6.08 (s,1H), 7.28 (s, 4H), 7.89 (s, 2H).

EXAMPLE 52-(3,5-Dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-one-5-thione(Compound No. 7)

To 100 ml of toluene was added 2.58 g of the starting compound 3,5-dioneas well as ½ equivalent of Lawesson's reagent and the mixture wasrefluxed for 5 hours. The reaction mixture was then concentrated andpurified by column chromatography (Merck Silica Gel 60; chloroform) toprovide 0.9 g of light-yellow crystals, m.p. 200-201° C.

Elemental analysis for C₉H₅Cl₂N₃OS

C H N Calcd.: 39.43; 1.84; 15.33 Found: 39.45; 1.97; 15.05

NMR [CDCl₃] δ: 7.67 (s, 3H), 7.84 (s, 1H), 13.80 (br, 1H).

EXAMPLE 6 2-(3,5-Dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(Compound No. 1)

In 50 ml of 70% ethanol was dissolved 2.74 g of Compound No. 7,synthesized in Example 5, followed by addition of 10 equivalents ofactivated Raney nickel. The mixture was stirred at room temperatureovernight, after which the insoluble matter was filtered off. Thefiltrate was concentrated under reduced pressure and the residue wasdissolved in 100 ml of ethyl acetate. This solution was dehydrated overanhydrous magnesium sulfate, concentrated and the resulting red-brownoil was purified by column chromatography (Merck Silica Gel 60;chloroform) to provide 1.0 g of the title compound as a pale yellowsubstance. m.p. 179-181° C.

Elemental analysis for C₉H₇Cl₂N₃O

C H N Calcd.: 44.29; 2.89; 17.22 Found: 44.59; 2.98; 17.41

NMR [CDCl₃] δ: 4.05-4.20 (m, 2H), 6.30-6.60 (br, 1H), 7.00-7.30 (m, 2H),7.52 (d, J=2 Hz, 2H).

EXAMPLE 72-(3,5-Dichlorophenyl)-5-phenyl-2,3-dihydro-1,2,4-triazin-3-one(Compound No. 27)

In 50 ml of dioxane was dissolved 2.20 g of2-(3,5-dichlorophenyl)semicarbazide followed by addition of 1.52 g ofphenylglyoxal monohydrate, and the mixture was refluxed for 5 hours. Thereaction mixture was then concentrated and the residue wasrecrystallized from acetonitrile to provide 1.34 g of the titlecompound. m.p. 160-161° C.

Elemental analysis for C₁₅H₉Cl₂N₃O

C H N Calcd.: 56.63; 2.85; 13.21 Found: 56.52; 2.78; 13.34

NMR [CDCl₃] δ: 7.38 (t, J=2 Hz, 1H), 7.45-7.70 (m, 3H), 7.75 (d, J=2 Hz,2H), 8.05-8.30 (m, 2H), 8.48 (s, 1H).

EXAMPLE 8

Starting with2-(3,5-dichlorophenyl)-1-(2-hydroxy-2-methylpropylidene)semicarbazone,Compound 2 was synthesized in otherwise a similar manner as Example 2.m.p. 120-122° C.

EXAMPLE 9

Starting with2-(3,5-dichlorophenyl)-1-(2-hydroxy-2-methylthioethylidene)semicarbazone,Compound 3 was synthesized in otherwise a similar manner as Example 2.m.p. 115-116° C.

EXAMPLE 10

Starting with2-(3,5-dichlorophenyl)-1-(2,2-dimethylthio-2-hydroxyethyl)semicarbazide,Compound 4 was synthesized in otherwise a similar manner as Example 2.m.p. 151-152° C.

EXAMPLE 11

Starting with Compound 1, Compound 5 was synthesized in otherwise asimilar manner as Example 4. m.p. 148-149° C.

EXAMPLE 12

Starting with2-(3,5-dichlorophenyl)-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one-5-thione,Compound 6 was synthesized in otherwise a similar manner as Example 6.m.p. 164-165° C.

EXAMPLE 13

Starting with2-(3,5-dichlorophenyl)-4-methylhexahydro-1,2,4-triazin-3,5-dione,Compound 8 was synthesized in otherwise a similar manner as Example 5.m.p. 149-150° C.

EXAMPLE 14

Starting with 2-(3,5-dichlorophenyl)-hexahydro-1,2,4-triazin-3,5-dione,Compound 9 was synthesized in otherwise a similar manner as Example 5.m.p. 221-223° C. (dec).

EXAMPLE 15

Starting with2-(3,5-dichlorophenyl)-1-(2-hydroxy-2-phenylethyl)semicarbazide,Compound 10 was synthesized in otherwise a similar manner as Example 2.m.p. 164-165° C.

EXAMPLE 16

Starting with2-(3,5-dichlorophenyl)-1-(2-hydroxy-2-phenylethylidene)semicarbazone,Compound 11 was synthesized in otherwise a similar manner as Example 2.m.p. 139-140° C.

EXAMPLE 17

Starting with Compound 8, Compound 12 was synthesized in otherwise asimilar manner as Example 6. m.p. 210-211° C.

EXAMPLE 18

Starting with2-(3,5-dichlorophenyl)-6-methylhexahydro-1,2,4-triazin-3-one-5-thione,Compound 13 is synthesized in otherwise a similar manner as Example 6.

EXAMPLE 19

Using methyl mercaptan in place of sodium methoxide, Compound 14 wassynthesized in otherwise a similar manner as Example 1. m.p. 190-191° C.

EXAMPLE 20

Using benzyl mercaptan in place of sodium methoxide, Compound 15 wassynthesized in otherwise a similar manner as Example 1. m.p. 152-153° C.

EXAMPLE 215-chloro-2-(3,5-dichlorophenyl)-2,3-dihydro-1,2,4-triazine-3-one(compound No. 17)

In 30 ml of dichloromethane suspended with 1.00 g of2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dionefollowed by addition of 2-fold morlar each of carbone tetrachloride andtriphenylphosphine and refluxed for 12 hours. After the completion ofthe reaction, the resulted solution were purified by colomunchlomatography (Merck Silica Gel 60dichloromethane-carbontetrachloride=2:1). m.p. 148-149° C.

NMR [CDCl₃] δ: 7.42(t,J=2 Hz,1H), 7.66(d,J=2 Hz,2H), 7.91(s, 1H)

EXAMPLE 22

Using potassium fluoride in place of sodium methoxide, Compound 18 wassynthesized in otherwise a similar manner as Example 1. m.p. 93-95° C.

EXAMPLE 23

Using p-chlorothiophenol in place of sodium methoxide, Compound 19 wassynthesized in otherwise a similar manner as Example 1. m.p. 176-178° C.

EXAMPLE 24

Using t-butyl mercaptan in place of sodium methoxide, Compound 20 wassynthesized in otherwise a similar manner as Example 1. m.p. 97-99° C.

EXAMPLE 25

Using potassium t-butoxide in place of sodium methoxide, Compound 21 wassynthesized in otherwise a similar manner as Example 1. m.p. 91-92° C.

EXAMPLE 26

Using phenol in place of sodium methoxide, Compound 22 was synthesizedin otherwise a similar manner as Example 1. m.p. 126-127° C.

EXAMPLE 27

Using cyclopropylmethamol in place of sodium methoxide, Compound 23 wassynthesized in otherwise a similar manner as Example 1. m.p. 68-69° C.

EXAMPLE 28

Using 2-fluoroethanol in place of sodium methoxide, Compound 24 wassynthesized in otherwise a similar manner as Example 1. m.p. 110-111° C.

EXAMPLE 29

Using 2,2,2-trifluoroethanol in place of sodium methoxide, Compound 25was synthesized in otherwise a similar manner as Example 1. m.p. 80-81°C.

EXAMPLE 30

Using 1,3-dimercaptopropane in place of sodium methoxide, Compound 26was synthesized in otherwise a similar manner as Example 1. m.p.195-196° C.

EXAMPLE 31

Starting with2-(3,5-dichlorophenyl)-5-chloro-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneand using methyl mercaptan in place of sodium methoxide, Compound 3 wassynthesized in otherwise a similar manner as Example 1. m.p. 115-116° C.

EXAMPLE 32

Using 2-(3,5-dichlorophenyl)-1-benzoylmethylidenesemicarbazone, Compound27 was synthesized in otherwise a similar manner as Example 2. m.p.160-161° C.

EXAMPLE 33

Using 2-(3,5-dichlorophenyl)-1-benzoyl-1-phenylmethylidenesemicarbazone,Compound 28 was synthesized in otherwise a similar manner as Example 2.m.p. 158-159° C.

EXAMPLE 34

Starting with2-(3,5-dichlorophenyl)-5-chloro-1,2,3,6-tetrahydro-1,2,4-triazin-3-oneand using methyl mercaptan in place of sodium methoxide, Compound 29 wassynthesized in otherwise a similar manner as Example 1. m.p. 133-134° C.

EXAMPLE 35

Using 2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-dione, Compound 30was synthesized in otherwise a similar manner as Example 5. m.p.183-184° C.

EXAMPLE 36

Starting with 2-phenyl-5-chloro-2,3-dihydro-1,2,4-triazin-3-one andusing methyl mercaptan in place of sodium methoxide, Compound 31 wassynthesized in otherwise a similar manner as Example 1. m.p. 115-116° C.

EXAMPLE 37

Starting with 2-phenyl-5-chloro-2,3-dihydro-1,2,4-triazin-3-one,Compound 32 was synthesized in otherwise a similar manner as Example 1.m.p. 102-103° C.

EXAMPLE 38

Using 2-(4-chlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-dione,Compound 33 was synthesized in otherwise a similar manner as Example 5.m.p. 198-199° C.

EXAMPLE 39

Starting with2-(4-chlorophenyl)-5-chloro-2,3-dihydro-1,2,4-triazin-3-one and usingmethyl mercaptan in place of sodium methoxide, Compound 34 wassynthesized in otherwise a similar manner as Example 1. m.p. 168-169° C.

EXAMPLE 40

Using 2-(4-chlorophenyl)-5-chloro-2,3-dihydro-1,2,4-triazin-3-one,Compound 35 was synthesized in otherwise a similar manner as Example 1.m.p. 151-152° C.

EXAMPLE 41

Using2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)-phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-dione,Compound 36 was synthesized in otherwise a similar manner as Example 5.m.p. 249-250° C.

EXAMPLE 42

Using2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)-phenyl]hexahydro-1,2,4-triazin-3,5-dione,Compound 37 was synthesized in otherwise a similar manner as Example 5.m.p. 215-216° C. (dec).

EXAMPLE 43

Using2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)-phenyl]-4-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one-5-thione,Compound 40 was synthesized in otherwise a similar manner as Example 6.m.p. 137-138° C.

EXAMPLE 44

Using2-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)-phenyl]-5-chloro-2,3-dihydro-1,2,4-triazin-3-one,Compound 42 was synthesized in otherwise a similar manner as Example 1.m.p. 193-194° C.

EXAMPLE 45

Compound 36 was dissolved in THF and reacted with equimolar of methyliodide to provide Compound 43. m.p. 204-205° C.

EXAMPLE 46

Compound 43 was dissolved in dichloromethane and reacted with chlorinegas to provide Compound 44. m.p. 184-185° C.

EXAMPLE 47 2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 1)

In 20 ml acetonitrile was dissolved 1.77 g of3,5-dichlorophenylhydrazine followed by addition of 1.10 g benzaldehydedropwise with constant stirring at 10 to 20° C. and obtained 2.70 ghydrazone. In 30 ml of acetonitrile was dissolved 1.33 g of thehydrazone followed by the addition of 3-fold mole pyridine, and 0.6-foldmole trichlolomethylchloroformate was added dropwise to the mixture withconstant stirring at 0 to 10° C. After completion of the dropwiseaddition, the mixture was stirred at 20 to 25° C. for 1 hour.

In 30 ml acetonitrile was dissolved 0.60 g of aminoacetoaldehydedimethyl acetate followed by the addition of the above prepared reactionsolution with constant stirring at 5 to 10° C. After completion of thedropwise addition, the reaction solution was stirred at 20 to 25° C. for3 hours. After concentrated the thus obtained reaction solution, icedwater was added and extracted with 50 ml of dichloromethane. After driedover anhydrous magnesium sulfate, the extract was concentrated andpurified by column chromatography (Merck Silica Gel 60; chloroform) toprovide 1.54 g of1-benzilidene-2-(3,5-dichlorphenyl)-4-(2,2-dimethoxyethyl)semicarbazoneas white crystals (m.p. 119-120° C.).

In 20 ml acetonitrile was dissolved 1.00 g of the thus obtainedsemicarbazone, followed by heat-reaction at 50 to 60° C. with 0.1 mlconc. hydrochloride for 20 minutes. After completed the reaction, theresulted crystal was collected by filtration and washed with water. Thusobtained crystal was recrystallized from ethyl acetate to provide 0.72 gthe title compound. m.p. 179-181° C. N.

EXAMPLE 482-[3,5-dichloro-4-(4-chlorophenylthio)phenyl]-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 45)

After refluxed 1.60 g of3,5-dichloro-4-(4-chlorophenylthio)phenylhydrazone and 0.9 g ofN-acetonylphenylcarbamate in 30 ml toluene, 0.8 g of1,8-diazabicyclo[5,4,0]-7-undensen was added therein and refluxed 2 morehours. After completed the reaction, the solution was concentrated,added ice water and extracted from 50 ml of dichloromethane. After driedover with anhydrous magnesium sulfate, the extract was concentrated todryness and purified by column chromatography (Merck Silica Gel 60;chloroform) to provide 0.34 g of the title compound as a whitesubstance. m.p. 258-259° C.

NMR (d₆-DMSO)δ: 2.04(s,3H), 3.98(br-d,J=2 Hz,2H), 7.22(g,J=8 Hz,4H),7.80(br,1H), 7.88(s,2H).

EXAMPLE 492-[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 46)

Starting with 3,5-dichloro-4-(4-chlorobenzoyl)phenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 48.m.p. 257-259° C.

EXAMPLE 504-acetyl-2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 47)

The title compound was obtained by acetylating the compound 46 preparedaccording to Example 49 with acetic acid anhydride in toluene. m.p.101-102° C.

EXAMPLE 512-(3,5-dichlorophenyl)-1-methyl-hexahydro-1,2,4-triazin-3-one(compoundNo. 49)

Chrystals obtained by reacting1-aminoacethyl-1-methyl-2-(3,5-dichrolophenyl) hydrazine with phenylchloroformate under the existance of a base was dissolved in THFfollowed by reduction with NaBH₄ to provide the title compound m.p.150-151° C.

EXAMPLE 526-chloro-2-(3,5-dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-thione(compound No. 49)

In 30 ml dichloromethane 1.33 g of1-(3,5-dichlorophenyl)-2-benzyldenhydrazone and 5-fold molar pyridinewere dissolved followed by addition of 2-fold molar thiophosgen dropwisewith constant stirring at 5 to 10° C. After completed the dropwiseaddition, the resulting solution was stirred at 20 to 25 for 1 hour andadded the equimolar ethylglcinate hydrochloride salt with stirring at 5to 10° C. After two hour reaction, the reaction solution was washed withwater and concentrated to dryness. The residue was dissolved in 30 ml ofacetonitrile and reacted with 0.1 ml conc. hydrochloride at 50 to 60° C.for 20 minutes to provide2-(3,5-dichlorophenyl)-hexahydro-1,2,4-triazin-6-one-3-thion. Theresulted compound was chlorized by known manner to provided the titlecompound. m.p. 207-208° C.

EXAMPLE 532-[3,5-dichlorophenyl)-1,5-dimethylhexahydro-1,2,4-triazin-3-one(compound No. 50)

Reacting 1-(2-aminopropyl)-1-methyl-2-(3,5-dichlorophenyl)hydrazine withphenyl chloroformate under presence of base to provide the titlecompound. m.p. 129-130° C.

EXAMPLE 542-(3,5-dichlorophenyl)-1-methyl-hexahydro-1,2,4-triazin-3-thione(compound No. 51)

Starting with 1-(2-aminoethyl)-2-(3,5-dichlorophenyl)methylhydrazide andthiophosgene, the title compound was synthesized in otherwise a similarmanner as Example 52. m.p. 240-241° C.

EXAMPLE 552-[3-chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 52)

Starting with3-chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 192-193° C.

EXAMPLE 562-[3-Chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenyl]-hexahydro-1,2,4-triazin-3-one(compound No. 53)

Reducing the compound 52 prepared according to Example 55 with LiAlH₄ inTHF to provide the title compound. m.p. 201-202° C.

EXAMPLE 572-[3-chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one-5-thione(compound No. 54)

Starting with2-[3-chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione,the title compound was synthesized in otherwise a similar manner asExample 5. m.p. 234-236° C.

NMR (d₆-DMSO)δ: 2.41(s,3H), 6.36(s,1H), 7.17-7.70(m,6H), 7.87(s,1H),13.86(br,1H).

EXAMPLE 582-[3-chloro-4-(4′-chloro-1-cyanobenzyl)-5-methylphenyl]hexahydro-1,2,4-triazine-3-one-5-thione(compound No. 55)

Reducing the compound 54 prepared according to Example 57 with LiALH₄ inTHF to provide the title compound. m.p. 217-218° C.

EXAMPLE 592-[3,5-dichloro-4-(4′-chloro-1-benzoyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 56)

Starting with 3,5-dichloro-4-(4′-chlorobenzoyl)phenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 212-213° C.

EXAMPLE 602-[3,5-dichloro-4-(4′-chloro-1-hydroxybenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 57)

Reducing the compound 56 prepared according to Example 59 with LiAlH₄ inTHF to provide the title compound. m.p. 115-116° C.

EXAMPLE 612-[3-chloro-4-(4-chlorobenzoyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 58)

Starting with 3-chloro-4-(4-chlorobenzoyl)phenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 158-159° C.

EXAMPLE 622-[3-chloro-4-(4′-chloro-1-hydroxybenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 59)

The compound 58 prepared according to Example 61 was reduced with LiAlH₄in THF to provide the title compound. m.p. 135-136° C.

EXAMPLE 632-[3,5-dichloro-4-(4-chlorophenylthio)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 60)

Starting with 3,5-dichloro-4-(4-chlorophenylthio)phenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 224-225° C.

EXAMPLE 642-[4-(4-chlorobenzyl)-3-chlorophenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 61)

Starting with 3-chloro-4-(4-chlorobenzyl)phenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 196-197° C.

EXAMPLE 652-[3-chloro-4-(2-chloropyridin-5-yl-cyanomethyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 62)

Starting with3-chloro-4-(2-chloropyridin-5-yl-cyanomethyl)-5-methylphenylhydrazine,the title compound was synthesized in,otherwise a similar manner asExample 47. m.p. 211-212° C.

EXAMPLE 662-[3-chloro-4-(2-chlorothiazol-5-yl-cyanomethyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 63)

Starting with3-chloro-4-(2-chlorothiazol-5-yl-cyanomethyl)-5-methylphenylhydrazine,the title compound was synthesized in otherwise a similar manner asExample 47. m.p. 238-239° C.

EXAMPLE 672-[3-chloro-4-(1-methylimidazol-2-yl-thio)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 64)

Starting with3-chloro-4-(1-methylimidazol-2-yl-thio)-5-methylphenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 173-174° C.

EXAMPLE 682-[3,5-dichloro-4-(4′-chloro-1-fuluorobenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 65)

In 20 ml dichloromethane was suspended 0.38 g of the compound 57followed by addition of 0.16 g of diethylaminosulfurtrifuluoride (DAST)dissolved in 5 ml dropwise with constant stirring at about −50° C. Afterreacted for 30 minutes under same condition, the reaction solution wasfurther reacted at 20-25° C. for 1 hour and concentrated. The residuewas purified by column chromatography (Merck Silica Gel 60; chloroform)to provide 0.22 g of the title compound. m.p. 182-183° C.

NMR (CDCl₃) δ: 4.09(t,J=2 Hz,2H), 6.65(br,1H), 7.12(t,J=2H₂,1H),7.22(d,J=46 Hz,1H), 7.30(s,4H), 7.67(d,J=2 Hz,2H).

EXAMPLE 692-[3-chloro-4-(4-chloro-1-fuluorobenzyl)pheny]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 66)

Starting with2-(3-chloro-4-(4′-chloro-1-hydroxybenzyl)pheny]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one,the title compound was synthesized in otherwise a similar manner asExample 68. m.p. 124-125° C.

EXAMPLE 702-[3,5-dichloro-4-(4′-chlorobenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 67)

Starting with 3,5-dichloro-4-(4-chlorobenzyl)phenylhydrazine the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 196-197° C.

EXAMPLE 712-[3,5-dichloro-4-(4-chlorophenylthio)phenyl]hexahydro-1,2,4-triazin-3-one(compound No. 68)

The compound 60 was reduced with LiAlH₄ in THF to provide the titlecompound. m.p. 242-243° C.

EXAMPLE 722-[4-(4-chlorobenzyl)-3-chlorophenyl]hexahydro-1,2,4-triazin-3-one(compound No. 69)

The compound 61 was reduced with LiAlH₄ in THF to provide the titlecompound. m.p. 157-158° C.

EXAMPLE 732-(2-chloro-4-trifluoromethylpyridin-6-yl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 70)

Starting with 2-chloro-4-trifluoromethylpyridin-6-yl-hydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 197-198° C.

EXAMPLE 742-(2-chloro-4-trifluoromethyl-pyridin-6-yl)hexahydro-1,2,4-triazin-3-one(compound No. 71)

The compound 70 prepared according to Example 73 was reduced with LiAlH₄in THF to provide the title compound. m.p. 191-192° C.

EXAMPLE 752-[3,5-dichloro-4-[2-(4-chlorophenyl)-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 72)

Starting with3,5-dichloro-4-[2-(4-chlorophenyl)-1-cyanoethyl]phenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 213-213° C.

EXAMPLE 762-[3,5-dichloro-4-(4′-chloro-1-methoxycarbonylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 73)

Starting with3,5-dichloro-4-(4′-chloro-1-methoxycarbonylbenzyl)phenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 206-207

EXAMPLE 772-[3,5-dichloro-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]hexahydro-1,2,4-triazin-3-one(compound No. 88)

The compound 73 prepared according to Example 76 was reduced with LiAlH₄in THF to provide the title compound. m.p. 108-109° C.

NMR (CDCl₃) δ; 3.00-3.60(br,4H), 4.00-4.70(br-m,4H), 5.12(t,1H),5.88(br-s,1H), 7.19(s,4H), 7.73(s,2H).

EXAMPLE 782-[3-trifluoromethyl-4-(4′-chloro-1-methoxycarbonylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 74)

Starting with3-trifluoromethyl-4-(4′-chloro-1-methoxycarbonylbenzyl)phenylhydrazine,the title compound was synthesized in otherwise a similar manner asExample 47. m.p. 118-119° C.

EXAMPLE 792-[3-chloro-4-(4-chlorobenzyl)-5-methylphenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 89)

Starting with 3-chloro-4-(4-chlorobenzyl)-5-methylphenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 209-210° C.

EXAMPLE 802-[3-chloro-4-(4-chlorobenzyl)-5-methylphenyl]hexahydro-1,2,4-triazin-3-one(compound No. 90)

The compound 89 prepared according to Example 79 was reduced with LiAlH₄in THF to provide the title compound. m.p. 197-198° C.

EXAMPLE 812-[3-chloro-4-(4′-chloro-1-fluorobenzyl)-5-methylphenyl]hexahydro-1,2,4-triazin-3-one(compound No. 91)

Starting with3-chloro-4-(4′-chloro-1-fluorobenzyl)-5-methylphenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 160-161° C. (dec).

EXAMPLE 822-[3-chloro-4-(4′-chlorophenoxy)-5-methylphenyl]hexahydro-1,2,4-triazin-3-one(compound No. 92)

Starting with 3-chloro-4-(4′-chlorophenoxy)-5-methylphenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47 and reduced with LiAlH₄ in THF. m.p. 188-189° C.

EXAMPLE 832-[3-chloro-4-(4′-chlorobenzylthio)-5-methylphenyl]hexahydro-1,2,4-triazin-3-one(compound No. 93)

Starting with 3-chloro-4-(4′-chlorobenzylthio)-5-methylphenylhydrazine,the title compound was synthesized in otherwise a similar manner asExample 82. m.p. 165-167° C.

EXAMPLE 842-{3-chloro-4-[2-(4′-chlorophenyl)-2-cyanovinylen]-5-methylphenyl}-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 94)

Starting with3-chloro-4-[2-(4′-chlorophenyl)-2-cyanovinylene]-5-methylphenylhydrazine,the title compound was synthesized in otherwise a similar manner asExample 47. m.p. 250-251° C.

EXAMPLE 852-[3-trifluoromethyl-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 95)

The compound 74 prepared in Example 78 was reduced with LiAlH₄ in THF toprovide the title compound. m.p. 76-77° C.

Further reduction of the title compound in THF with LiAlH₄, and obtained2-[3-trifluoromethyl-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]-hexahydro-1,2,4-triazin-3-one(compound No. 77). m.p. 87-88° C.

EXAMPLE 862-[3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)phenyl]-6-methyl-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 39)

Starting with 3,5-dichloro-4-(4′-chloro-1-cyanobenzyl)phenylhydrazine isdisolved into toluene and heated with acetonylamine for two hours. Afteradding equimolar of phenyl chloroformate, the result solution was heatedfor farther two hours. After completion of the reaction, the reactionsolution is cooled and filtrated to provide the title compound ascrystal.

EXAMPLE 872-[3-trifluoromethyl-4-(4′-chloro-1-fluoromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 75)

Starting with compound 77, the title compound was synthesized inotherwise a similar manner as Example 68. m.p. 163-164° C.

EXAMPLE 882-[3,5-dichloro-4-(4′-chloro-1-methylthiomethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 96)

In methanol,2-[3,5-dichloro-4-(4′-chloro-1-chloromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneis reacted with sodium thiomethoxide to provide the title compound.

EXAMPLE 892-[3,5-dichloro-4-(4′-chloro-1-dimethylaminomethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 97)

In dimethylformamide,2-[3,5-dichloro-4-(4′-chloro-1-chloromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneis reacted with dimethylamine solution.

EXAMPLE 902-[3,5-dichloro-4-(4′-chloro-1-trifluoromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 98)

Starting with3,5-dichloro-4-(4′-chloro-1-trifluoromethylbenzyl)phenylhydrazine, thetitle compound is synthesized in otherwise a similar manner as Example47.

EXAMPLE 912-[3,5-dichloro-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound 99)

Starting with3,5-dichloro-4-(4′-chloro-1-hydroxymethylbenzyl)phenylhydrazine, thetitle compound is synthesized in otherwise a similar manner as Example47.

EXAMPLE 922-[3,5-dichloro-4-(4′-chloro-1-fluoromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 100)

Starting with2-[3,5-dichloro-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazine-3-one,the title compound is synthesized in otherwise a similar manner asExample 68.

EXAMPLE 932-[3,5-dichloro-4-(4′-chloro-1-chloromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 101)

In toluene,2-[3,5-dichloro-4-(4′-chloro-1-hydroxymethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneis heated with thionylchloride and purified to give the title compoundby a column chromatography.

EXAMPLE 942-[3,5-dichloro-4-(4′-chloro-1-methylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 102)

2-[3,5-dichloro-4-(4′-chloro-1-chloromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneis dissolved in acetic acid and refluxed with 5-fold molar zinc-powderfor 3 hours. After concentrated, iced water is added to the results andextracted with ethyl acetate. The extract is dried by MgSO₄ andconcentrated and purified by a column chromatography to provide thetitle compound.

EXAMPLE 952-[3,5-dichloro-4-(4′-chloro-1-methoxymethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 103)

In methanol,2-[3,5-dichloro-4-(4′-chloro-1-chloromethylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-oneis reacted with sodium methoxide to provide the title compound.

EXAMPLE 962-[3-trifluoromethyl-4-(4′-chloro-1-methylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one(compound No. 104)

In acetic acid is dissolved2-[3-trifluoromethyl-4-(4′-chloro-1-methylbenzyl)phenyl]-2,3,4,5-tetrahydro-1,2,4-triazin-3-onefollowed by addition of 5-fold molar Zinc powder and refluxed for 3hours with heated. After adding ice water, the reaction solution isextracted with ethyl acetate. The extract is dried with MgSO₄,concentrated and subjected to purification by column chromatography toprovide the title compound.

EXAMPLE 972-{4-[2-(4-chlorophenyl)-1-cyanovinyl]-3,5-dichlorophenyl}-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No. 87)

Starting with4-[2-(4-chlorophenyl)-1-cyanovinyl]-3,5-dichlorophenylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 83-85° C.

H-NMR (CDCl₃) δ; 4.12-4.17(2H,J=2.1 Hz,t), 5.83-5.86(1H,J=2.5 Hz,d),7.07-7.89(8H,m).

EXAMPLE 982-[3,5-dichloro-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl-methyl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No. 86)

Staring with3,5-dichloro-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl-methyl)phenylhydrazine,the title compound was synthesized in otherwise a similar manner asExample 47. m.p 164-165° C.

EXAMPLE 992-[4-(4-chloro-α-chloromethylbenzyl)-3-trifluoromethylphenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No.76)

Staring with Compound No.95, the title compound was synthesized inotherwise a similar manner as Example 68. m.p. 157-158° C.

EXAMPLE 1002-[3-chloro-4-(4-chloro-α-fluorobenzyl)-5-methylpheyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No.78)

Staring with Compound No.79, the title compound was synthesized inotherwise a similar manner as Example 68. m.p. 141-142° C. (dec.).

EXAMPLE 1012-[3-chloro-4-(4-chloro-α-hydroxybenzyl)-5-methylpheyl]-1,4,5,6-tetrahydro-1,2,4-triazin-3(2H)-one(compound No.80)

Staring with Compound No.81, Compound No.79 was synthesized in otherwisea similar manner as Example 60, followed by additon of excess sodiumborate to synthsize compound No. 80. m.p. 146-147° C.

EXAMPLE 1022-[3-chloro-4-(4-chlorobenzoyl)-5-methylpheyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No.81)

Starting with 3-chloro-4-(4-chlorobenzoyl)-5-methylpheylhydrazine, thetitle compound was synthesized in otherwise a similar manner as Example47. m.p. 171-172° C.

EXAMPLE 1032-[(3-chloro-4-(4-chlorobenzoyl)-5-methylpheyl]-1,2,4-triazin-3(2H)-one-5(4H)-thione(compound No.82)

Starting with2-[3-chloro-4-(4-chlorobenzoyl)-5-methylpheyl]-1,2,4-triazin-3,5(2H,4H)-dione,the title compound was synthesized in otherwise a similar manner asExample 5. m.p. 104-106° C.

H′-NMR[d6-DMSO] δ; 2.16(3H, s), 7.60-7.89 (7H, m), 13.89(1H, br-s).

EXAMPLE 1042-[(3-chloro-5-methyl-4-phenyl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(compound No. 83)

Starting with (3-chloro-5-methyl-4-phenyl)phenylhydrazine, the titlecompound was synthesized in otherwise a similar manner as Example 47.m.p. 175-176° C.

TABLE 3

Compound No.

X

 1

O —NH—CH₂— —N═CH—  2

O

—N═CH—  3

O

—N═CH—  4

O

—NH—CH₂—  5

O —NH—CH₂— —NH—CH₂—  6

O —NH—CH₂—

 7

O

—N═CH—  8

O

—NH—CH₂—  9

O

—NH—CH₂— 10

O

—NH—CH₂— 11

O

—N═CH— 12

O

—NH—CH₂— 13

O —NH—CH₂—

14

O

—N═CH— 15

O

—N═CH— 16

O

—N═CH— 17

O

—N═CH— 18

O

—N═CH— 19

O

—N═CH— 20

O

—N═CH— 21

O

—N═CH— 22

O

—N═CH— 23

O

—N═CH— 24

O

—N═CH— 25

O

—N═CH— 26

O

—N═CH— 27

O

—N═CH— 28

O

29

O

—NH—CH₂— 30

O

—N═CH— 31

O

—N═CH— 32

O

—N═CH— 33

O

—N═CH— 34

O

—N═CH— 35

O

—N═CH— 36

O

—N═CH— 37

O

—NH—CH₂— 38

O —NH—CH₂— —NH—CH₂— 39

O —NH—CH₂—

40

O

—NH—CH₂— 41

O —NH—CH₂— —N═CH— 42

O

—N═CH— 43

O

—N═CH— 44

O

—N═CH— 45

O —NH—CH₂—

46

O —NH—CH₂—

47

O

48

O —NH—CH₂—

49

S —NH—CH₂—

50

O

51

S —NH—CH₂—

52

O —NH—CH₂— —N═CH— 53

O —NH—CH₂— —NH—CH₂— 54

O

—N═CH— 55

O

—NH—CH₂— 56

O —NH—CH₂— —N═CH— 57

O —NH—CH₂— —N═CH— 58

O —NH—CH₂— —N═CH— 59

O —NH—CH₂— —N═CH— 60

O —NH—CH₂— —N═CH— 61

O —NH—CH₂— —N═CH— 62

O —NH—CH₂— —N═CH— 63

O —NH—CH₂— —N═CH— 64

O —NH—CH₂— —N═CH— 65

O —NH—CH₂— —N═CH— 66

O —NH—CH₂— —N═CH— 67

O —NH—CH₂— —N═CH— 68

O —NH—CH₂— —NH—CH₂— 69

O —NH—CH₂— —NH—CH₂— 70

O —NH—CH₂— —N═CH— 71

O —NH—CH₂— —NH—CH₂— 72

O —NH—CH₂— —N═CH— 73

O —NH—CH₂— —N═CH— 74

O —NH—CH₂— —N═CH— 75

O —NH—CH₂— —N═CH— 76

O —NH—CH₂— —N═CH— 77

O —NH—CH₂— —NH—CH₂— 78

O —NH—CH₂— —N═CH— 79

O —NH—CH₂— —N═CH— 80

O —NH—CH₂— —NH—CH₂— 81

O —NH—CH₂— —N═CH— 82

O

—N═CH— 83

O —NH—CH₂— —N═CH— 84

O —NH—CH₂— —N═CH— 85

O —NH—CH₂— —N═CH— 86

O —NH—CH₂— —N═CH— 87

O —NH—CH₂— —N═CH— 88

O —NH—CH₂— —NH—CH₂— 89

O —NH—CH₂— —N═CH— 90

O —NH—CH₂— —NH—CH₂— 91

O —NH—CH₂— —NH—CH₂ 92

O —NH—CH₂— —NH—CH₂— 93

O —NH—CH₂— —NH—CH₂— 94

O —NH—CH₂— —N═CH— 95

O —NH—CH₂— —N═CH— 96

O —NH—CH₂— —N═CH— 97

O —NH—CH₂— —N═CH— 98

O —NH—CH₂— —N═CH— 99

O —NH—CH₂— —N═CH— 100 

O —NH—CH₂— —N═CH— 101 

O —NH—CH₂— —N═CH— 102 

O —NH—CH₂— —N═CH— 103 

O —NH—CH₂— —N═CH— 104 

O —NH—CH₂— —N═CH—

FORMULATION EXAMPLE 1

2-(3,5-Dichlorophenyl)-5-methoxy-2,3-dihydro-1,2,4-triazin-3-one(Compound No. 18), 25 g, was pulverized to pass a 355 μm sievethoroughly and evenly blended with 975 g of defatted rice bran (1:1);

FORMULATION EXAMPLE 1

2-(3,5-Dichlorophenyl)-2,3,4,5-tetrahydro-1,2,4-triazin-3-one (CompoundNo. 1), 5.0 g, was dissolved in 10 cc of methanol, followed by additionof 100 g of soybean. After stirring, the mixture was dried in vacuo at50° C. for 10 hours. This mixture was crushed to pass a 500 μm sievethoroughly and blended uniformly with 895 g of soybean meal to provide acomposition.

The substituent designations of the formulae of the second embodimentare specific to the second embodiment and may be the same or differentthan the substituent designation according to the first embodiment.

BACKGROUND OF THE SECOND EMBODIMENT

1. Field of the Second Embodiment

This second embodiment relates to a novel method of producing triazinederivatives, and also relates to a novel semicarbazone derivative whichcan be employed in the method of this second embodiment. This secondembodiment also relates to a novel triazine derivative.

2. Description of the Prior Art

A 1,2,4-triazine derivative having a substituent at the 2-position hasbeen widely used as an agent for controlling pests in the fields ofmedicines, veterinary drugs and agricultural drugs. For example, asveterinary drugs, a report is found in JPA H2(1990)-240003 that thecompound is employable for controlling parasitic worms in fish andinsects, and, another report is found in JPA H5(1993)-1047 that thecompound is effective for controlling parasitic protozoa, especiallycoccidia. And, as agricultural chemicals, the effectiveness of thecompound as a herbicide is reported in WO-A-86/0072 (Jan. 3, 1986; FMCCo.).

As described thus above, 1,2,4-triazine derivatives having a substituentat 2-position, especially -3,5-dione derivatives and -3-one derivatives,are remarkably useful compounds for controlling pests. The presentinventors considered that finding of a method of producing thesecompounds simply and conveniently would make a contribution to socialwelfare, and started the present research work.

As methods of synthesizing a 1,2,4-triazine-3,5-dione derivative havinga substituent at the 2-position, a method which comprises allowing ahydrazone derivative to react with a keto-carboxylic acid[WO-A-86/00072] and a method which comprises allowing an activemethylene compound (e.g. cyanoacetylurethane) to react with diazoniumsalt then subjecting the reaction mixture to ring-closure,decarboxylation reaction to produce the object compound [Journal ofMedicinal Chemistry, Vol.22, p.1483, 1977] have been known. Thesemethods, however, are-accompanied with such drawbacks as having arelatively large number of reaction steps and requiring relativelydrastic reaction conditions, thus being difficult to conduct on anindustrial scale.

Especially no practical method of producing a 1,2,4-triazin-3-onederivative having a substituent at the 2-position has been known.

SUMMARY OF THE SECOND EMBODIMENT

The second embodiment is to provide a method of producing simply andconveniently triazine derivatives in a high yield which can be used asmedicines, veterinary drugs and agricultural chemicals. Another objectof the second embodiment is to provide novel semicarbazone derivatives(II) and hydrazone derivatives (I) which can be used in the productionof the triazine derivatives. Yet another object of the second embodimentis to produce novel 1,2,4-triazin-3-one derivatives which can be used asdescribed above.

In view of the above-described technical background, the presentinventors conducted extensively various studies for establishing amethod of producing, for example, a 2-substituted-1,2,4-triazin-3-onederivative in which the 5-position of the triazine ring isunsubstituted. As a result, we found that a2-substituted-1,2,4-triazine-3,5-dione derivative can be produced in ahigh yield by allowing a hydrazone derivative represented by the generalformula (I) as defined hereinafter to react with 2,2-dialkoxyethylisocyanate in the presence of a base, to produce a reaction mixturewhich contains a semicarbazone derivative. The reaction mixture is thensubjected to ring-closure reaction to produce a2-substituted-1,2,4-triazin-3-one derivative (III), followed bysubjecting thus-produced 2-substituted-1,2,4-triazine-3-one derivativeto oxidation to produce a 2-substituted-1,2,4-triazine-3,5-dionederivative. They have conducted further studies diligently to accomplishthe second embodiment.

DETAILED DESCRIPTION OF THE SECOND EMBODIMENT

More specifically, the second embodiment is to provide a semicarbazonederivative (II) represented by the formula:

wherein R¹ stands for an optionally substituted hydrocarbon residualgroup; R² and R³ independently stand for hydrogen, an optionallysubstituted hydrocarbon residual group or an electron withdrawing group;and R⁴ stands for an optionally substituted alkyl group, and, a methodof producing a 1,2,4-triazin-3-one derivative (III) represented by theformula

wherein R¹ is of the same meaning as defined above; X stands forcarbonyl group, thiocarbonyi group, an optionally substituted methylenegroup; and dashed line means that a double bond may optionally beformed, which is characterized by subjecting the said semicarbazonederivative (II) to ring-closure reaction.

In the above-mentioned formulae, as the optionally substitutedhydrocarbon residual groups shown by R¹, mention is made of, forexample, an aromatic ring, more specifically, an optionally substitutedaromatic homocyclic group and a 5- to 6-membered aromatic heterocyclicgroup optionally having at least one substituent.

Examples of the optionally substituted aromatic homocyclic group includeC₆₋₁₄ aryl groups such as phenyl, 1- or 2-naphthyl. Among them,preferable one is a phenyl group., Particularly preferable examples area phenyl substituted at 3- and 4-positions and a phenyl substituted at3-, 4- and 5-positions.

Examples of the 5- to 6-membered aromatic heterocyclic groups include-anunsaturated 5- to 6-membered cyclic group containing, besides carbonatoms, 1 to 4 hetero-atoms such as oxygen atom, sulfur atom and nitrogenatom, such as a 5-membered cyclic group containing, besides carbonatoms, 1 to 4 hetero-atoms selected from oxygen atom, sulfur atom andnitrogen atom, e.g. 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3-or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl and 1H- or 2H-tetrazolyl, and, a 6-membered cyclic groupcontaining, besides carbon atoms, 1 to 4 hetero-atoms selected fromoxygen atom, sulfur atom and nitrogen atom, e.g. 2-, 3- or 4-pyridyl,N-oxido-2, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or5-pyrimidinyl, dioxotriazinyl, pyranyl, thiopyranyl, 1,3-oxazinyl,1,4-thiazinyl, 1,3-thiazinyl, triazinyl, oxotriazinyl, 3- or4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl. Among them, a6-membered ring containing one hetero-atom is preferable, and aN-containing hetero-ring, for example, is especially preferable.

Such aromatic homocyclic or heterocyclic groups as above may optionallyhave, at any possible position, 1 to 5, preferably 1 to 3 substituentsselected from, for example,

(1) C₁₋₄ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl,

(2) C₂₋₄ alkenyl groups such as vinyl, 1-methylvinyl, 1-propenyl andallyl,

(3) C₇₋₁₁ aralkyl groups such as benzyl, α-methylbenzyl, α-cyanobenzyl,α-hydroxybenzyl and phenethyl,

(4) phenyl group,

(5) C₁₋₆ alkoxy groups such as methoxy, ethoxy, propoxy, iso-propoxy,n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy group,

(6) phenoxy group,

(7) C₁₋₆ alkanoyl groups such as formyl, acetyl, propionyl, n-butyryland iso-butyryl group,

(8) benzoyl group,

(9) carboxyl group,

(10) C₂₋₇ alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl and tert-butoxycarbonyl group,

(11) carbamoyl group,

(12) N-mono-C₁₋₄ alkylcarbamoyl groups such as N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl andN-butylcarbamoyl,

(13) N,N-di-C₁₋₄ alkylcarbamoyl groups such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl and N,N-dibutylcarbamoyl,

(14) halogen atoms such as fluorine, chlorine, bromine and iodine,

(15) mono-, di- or tri-halogeno-C₁₋₄ alkyl groups such as chloromethyldichloromethyl, trifluoromethyl and trifluoroethyl,

(16) optionally protected amino groups,

(17) mono-C₁₋₄ alkylamino groups such as methylamino, ethylamino,propylamino, isopropylamino and butylamino,

(18) C₁₋₆ alkanoylamino groups such as formamido, acetamino,trifluoroacetamido, propionamido, butylamido and isobutylamido,

(19) benzoylamino groups such as benzamido,

(20) carbamoylamino group,

(21) N—C₁₋₄ alkyl carbamoylamino groups such as N-methyl carbamoylamino,N-ethyl carbamoylamino, N-propyl carbamoylamino, N-isopropylcarbamoylamino and N-butyl carbamoylamino,

(22) N,N-di-C₁₋₄ alkyl carbamoylamino groups such as N,N-dimethylcarbamoylamino, N,N-diethyl carbamoylamino, N,N-dipropyl carbamoylaminoand N,N-dibutyl carbamoylamino,

(23) C₁₋₃ alkylenedioxy groups such as methylenedioxy and ethylenedioxygroup,

(24) hydroxy group,

(25) nitro group,

(26) cyano group,

(27) mercapto group,

(28) sulfo group,

(29) sulfino group,

(30) phosphono group,

(31) sulfamoyl group,

(32) C₁₋₆ monoalkyl sulfamoyl groups such as N-methyl sulfamoyl, N-ethylsulfamoyl, N-propyl sulfamoyl, N-isopropyl sulfamoyl and N-butylsulfamoyl,

(33) di-C₁₋₄ alkyl sulfamoyl groups such as N,N-dimethyl sulfamoyl,N,N-diethyl sulfamoyl, N,N-dipropyl sulfamoyl and N,N-dibutyl sulfamoyl,

(34) C₁₋₆ alkylthio groups such as methylthio, ethylthio, propylthio,isopropylthio, n-butylthio, sec-butylthio and tert-butylthio group,

(35) phenylthio group,

(36) C₁₋₆ alkyl sulfinyl groups such as methyl sulfinyl, ethyl sulfinyl,propyl sulfinyl and butyl sulfinyl,

(37) phenyl sulfinyl group,

(38) C₁₋₆ alkyl sulfonyl groups such as methyl sulfonyl, ethyl sulfonyl,propyl sulfonyl and butyl sulfonyl group,

(39) phenyl sulfonyl group, and

(40) a 5- or 6-membered heterocyclic group containing, besides carbonatoms, 1 to 4 hetero-atoms selected from oxygen atom, sulfur atom andnitrogen atom, which may optionally be linked to the above-mentionedaromatic cyclic group through 1 to 4 carbon atoms, oxygen atoms,nitrogen atoms and atomic chain consisting of, for example, oxygen atom,such as 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl, N-oxido-2-, 3- or 4-pyridyl, 2-,4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, oxoimidazinyl,dioxotriazinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,1,3-thiazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyland N-oxido-3- or 4-pyridazinyl.

Among the above-mentioned hydrocarbon residual groups shown by R¹,optionally substituted phenyl groups are preferable. Especiallypreferable examples of such substituents include an optionallysubstituted C₇₋₁₁ aralkyl groups (3) and/or halogen atom (14). Thephenyl having substituents at 3- or/and 5-positions and 4-position, andthe phenyl having substituents at 3- and/or 5-position and 4-positionare especially preferable.

Among these groups, those having carbon chain or cyclic group containingtwo or more carbon atoms may optionally have, at any possible position,further one to four, preferably one or two substituents selected from,for example,

(a) halogen atoms such as chlorine, fluorine, bromine and iodine,

(b) hydroxy group,

(c) C₁₋₄ alkoxy groups such as methoxy and ethoxy, or oxo group,

(d) di-C₁₋₄ alkylamino groups such as dimethylamino and diethylamino,

(e) halogeno-C₁₋₄ alkyl groups such as chloromethyl, 1-chloroethyl,1-fluoroethyl, fluoromethyl, trifluoromethyl and trifluoroethyl,

(f) C₁₋₇ acyl groups such as formyl, acetyl, propionyl, isopropionyl,trifluoroacetyl and benzoyl,

(g) hydroxy-C₁₋₄ alkyl groups such as hydroxymethyl, 1-hydroxyethyl and2-hydroxyethyl,

(h) C₁₋₄ alkoxy-C₁₋₄ alkyl groups such as methoxymethyl, 1-methoxyethyl,1-ethoxyethyl, acetoxyethyl and 2-ethoxyethyl,

(i) C₁₋₅ sulfamoyl groups such as aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl and morpholynosulfonyl,

(j) C₁₋₇ carbamoyl group such as aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl and phenylaminocarbonyl

(k) C₂₋₄ alkyl groups such as ethyl and isopropyl,

(l) carboxyl group,

(m) C₁₋₇ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyland phenoxycarbonyl.

For example, in the case that the C₇₋₁₁ aralkyl group (3) is benzyl, thebenzyl substituted at its 4-position with the substituent (f) or (g) ispreferable.

In the above formulae, as the optionally substituted hydrocarbonresidual groups shown by R² or R³, mention is made of, for example,optionally substituted alkyl groups and optionally substituted aromatichomocyclic groups or 5- to 6-membered aromatic heterocyclic groups.

Among them, as the alkyl group, use is preferably made of C₁₋₄ loweralkyl groups (e.g. methyl), as the aromatic homocyclic group, use ispreferably made of phenyl group, and, as the aromatic heterocyclicgroups, use is preferably made of 2-, 3- or 4-pyridyl group.

Examples of the electron withdrawing groups shown by R² or R³ includecyano group, C₁₋₆ alkoxy-carbonyl such as methoxy carbonyl and ethoxycarbonyl, hydroxy carbonyl, C₆₋₁₀ aryloxy carbonyl groups such asphenyloxy carbonyl and naphthyloxy carbonyl, a 5- or 6-memberedheterocyclic-oxycarbonyl group containing, besides carbon atoms, 1 to 4hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom,such as pyridyloxy carbonyl and thienyloxy carbonyl, C₁₋₆ alkyl sulfonylgroups optionally substituted with one to three halogen atoms selectedfrom, for example, chlorine, bromine and fluorine, such as methylsulfonyl, trifluoromethyl sulfonyl and ethyl sulfonyl, amino sulfonyl,di-C₁₋₄ alkoxy phosphoryl groups such as dimethoxyphosphoryl,diethoxyphosphoryl and dipropoxyphosphoryl, C₁₋₆ acyl groups optionallysubstituted with one to three halogen atoms selected from chlorine,bromine and fluorine, such as acetyl and propionyl, carbamoyl, and C₁₋₆alkyl-sulfonyl thiocarbamoyl groups such as methyl sulfonylthiocarbamoyl and ethyl sulfonyl thiocarbamoyl group.

As the preferable example of R² and R³, mention is made of hydrogen asone of R² and R³ and phenyl as the other.

Further, R² and R³ may optionally be combined with each other to form a4- to 7-membered ring such as preferably cycloalkyl groups. Other 4- to7-membered rings such as optionally substituted aryl, arylalkyl,homocyclic and heterocyclic rings are also contemplated by the presentinvention.

Examples of the optionally substituted alkyl groups shown by R⁴ includeC₁₋₄ alkyl groups, and especially methyl and ethyl are preferable. OneR⁴ and the other R⁴ may be optionally conbined with each other to form aring with an alkylene chain (e.g. CH₂₂).

In the production method of this invention, the intermediate compound, asemicarbazone derivative (II), can be produced by the method as shownbelow.

The reaction step of producing the intermediate semicarbazone derivative(II) by allowing a hydrazone derivative (I) to react with2,2-dialkoxyethyl isocyanate, which is shown by the following reaction:

wherein R¹, R², R³ and R⁴ are of the same meaning as defined above, isconducted usually in an inert solvent or in the absence of solvent,optionally in the presence of a base. While the reaction temperaturevaries with the kinds of solvents employed, it ranges usually from about−20 to 110° C., especially preferably from about 0 to 50° C. While thereaction time varies with the kinds of solvents employed, it rangesusually from about 10 minutes to 5 hours, preferably from 30 minutes to2 hours.

As the solvent for this reaction, almost all inert solvents can beemployed, i.e. solvents commonly employed in the general chemicalreactions, as exemplified by benzene, ligroin, benzine, toluene, xylene,methylene chloride, ethylene chloride, chloroform, carbon tetrachloride,dichloroethane, chlorobenzene, o-dichlorobenzene, ethers (e.g. diethylether, diisopropyl ether, dibutyl ether, glycol dimethyl ether, diglycoldimethyl ether, tetrahydrofuran and dioxane), ketone (e.g. acetone,methyl ethyl ketone, methyl isopropyl ketone and methyl isopropylketone), ester (e.g. ethyl acetate ester), nitrile (e.g. acetonitrileand propionitrile), amide (e.g. dimethylformamide, dimethylacetamide andhexamethyl phosphoric triamide), dimethyl sulfoxide and pyridine.

The amount of 2,2-dialkoxy ethyl isocyanate ranges usually from 1.0 to3.5 mol., preferably from 1.0 to 1.5 mol., relative to the hydrazonederivative (I).

For allowing the reaction to proceed smoothly, a base may optionally beadded. Examples of the base to be employed for this purpose includeinorganic bases such as sodium carbonate, potassium carbonate, calciumcarbonate, sodium hydroxide and potassium hydroxide, and organic basessuch as triethylamine, pyridine, dimethyl aniline, picoline,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]-7-undecene (DBU). The amount of the base to beemployed ranges from 0.001 to 30.0%, weight percent preferably from 0.01to 5.0%, relative to the starting material (I).

Among the semicarbazone derivative (II) obtained by the above method, R¹is defined as the derivative (II′) having a residual group:

wherein R² is acyl, optionally substituted sulfamoyl, optionallysubstituted carbamoyl, carboxyl, alkoxycarbonyl, optionally substitutedalkyl or optionally substituted amino; A is —CH— or nitrogen atom, Y′ ismethylene, cyanomethylene, carbonyl, hydroxymethylene, sulfur atom,sulfinyl, sulfonyl or oxygen atom; Hal is halogen (e.g. chlorine), R^(b)hydrogen, halogen (e.g . chlorine) or lower alkyl (e.g. methyl). Thisderivative (II) is a novel compound and important intermediate forobtaining useful 1,2,4-triazine-3-one derivative (III).

The semicarbazone derivative (II) synthesized by the above-describedreaction is subjected to a ring-closure reaction by a conventionalmethod to convert into a 2-substituted-1,2,4-triazin-3-one derivative(III).

The derivative (III) includes the derivatives (III-a), (III-b), (III-c),(III-d) and (III-e). Each derivative can be produced by the followingsteps.

[the simbols are the same as defined before]

The 2-substituted-1,2,4-triazine-3-one derivative (III-a) is produced byring-closure reaction of the semicarbazone derivative (II) and the2-substituted-1,2,4-triazine-3,5-dione derivative (III-b) is produced byoxidation reaction of the derivative (III-a). The2-substituted-1,2,4-triazine-3-one-5-thione derivative (III-c) isobtainable by thiolation reaction of the derivative (III-b). The2-substituted-5-mono (or di) substituted-1,2,4-triazin-3-one (III-d) isproducible from the derivative (III-c) or (III-b). Thus obtainedderivative (III-a), (III-b), (III-c) or (III-d) is subjected toreduction reaction to obtain the derivative (III-e) in high yield.

The reaction (II)-(II-a) is conducted usually in an inert solvent or inthe absence of solvent, optionally in the presence of an acid. While thereaction temperature varies with the kinds of solvents employed for thereaction, it ranges usually from about −20 to 150° C., especially fromabout 0 to 80° C. While the reaction time varies with the kinds ofsolvents employed for the reaction, it ranges usually from about 10minutes to 5 hours, preferably from 30 minutes to 2 hours.

As the solvent for this reaction, almost all inert solvents can beemployed, i.e. solvents commonly employed in the general chemicalreactions, as exemplified by benzene, ligroin, benzine, toluene, xylene,methylene chloride, ethylene chloride, chloroform, carbon tetrachloride,dichloroethane, chlorobenzene, o-dichlorobenzene, ethers (e.g. diethylether, diisopropyl ether, dibutyl ether, glycol dimethyl ether, diglycoldimethyl ether, tetrahydrofuran and dioxane), ketone (e.g. acetone,methyl ethyl ketone and methyl isopropyl ketone), ester (e.g. ethylacetate ester), nitrile (e.g. acetonitrile and propionitrile), amide(e.g. dimethylformamide, dimethylacetamide and hexamethyl phosphoricacid triamide), alcohol (e.g. methyl alcohol, ethyl alcohol propylalcohol, isopropyl alcohol), pyridine and dimethyl sulfoxide.

In the reaction of converting a semicarbazone derivative (II) to a2-substituted-1,2,4-triazin-3-one derivative by ring-closure reaction,an acid or a Lewis acid may be added for the purpose of allowing thereaction to proceed smoothly. Examples of the acid employed for thispurpose include trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methane sulfonic acid, sulfuric acid, hydrochloric acid,phosphoric acid and polyphosphoric acid and example of the Lewis acid istrifluoroborane etherate.

In the production method of this invention, the object1,2,4-triazin-3-one derivative (III) can be produced in a high yield bysubjecting the reaction mixture to ring-closure reaction, withoutisolating the semicarbazone derivative (II) from the reaction mixtureobtained by the above-mentioned reaction a). This one-pot reaction ispreferably employed for producing the object compound (III) on anindustrial scale.

The 1,2,4-triazin-3-one derivative (III-a) produced by theabove-described reaction step can be used per se as agriculturalchemicals and drugs for controlling parasitic pest. By subjecting thesecompounds to further reaction such as oxidation, reduction andsubstitution in accordance with conventional methods, various triazinederivatives such as 1,2,4-triazine-3,5-dione derivatives,1,2,4-triazine-3-oxo-5-thione derivatives, 1,2,4-triazin-3-one-5-aminoderivative and hexahydro-1,2,4-triazin-3-one derivatives can be producedconveniently and in a high yield. For example, by employing a2-substituted-1,2,4-triazin-3-one derivative synthesized by theabove-described reaction step, a 2-substituted 1,2,4-triazine-3,5-dionederivative can be produced in a high yield by a conventional oxidationreaction. This oxidation reaction can be conducted by using a oxidizingagent described in, for example, I & II of Shin Jikken Kagaku Koza Vol.15 (compiled by The Chemical Society of Japan, Published by Maruzen Co.,Ltd., 1976).

This reaction is conducted usually in an inert solvent, optionally inthe presence of a base or an acid. While the reaction temperature varieswith the kinds of solvents, it ranges usually from about 20 to 180° C.,preferably from about 50 to 100° C. While the reaction time varies withthe kinds of solvents, it ranges usually from about one hour to 15hours, preferably from 3 hours to 8 hours. As the solvent for thisreaction, almost all inert solvents can be employed, i.e. solventscommonly employed in the general chemical reactions, as exemplified bybenzene, ligroin, benzine, toluene, xylene, methylene chloride, ethylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene, o-dichlorobenzene, ethers (e.g. dibutyl ether, glycoldimethyl ether, diglycol dimethyl ether, tetrahydrofuran and dioxane),ketone (e.g. methyl ethyl ketone, methyl isopropyl ketone and methylisopropyl ketone), ester (e.g. ethyl acetate ester), nitrile (e.g.acetonitrile and propionitrile), amide (e.g. dimethylformamide,dimethylacetamide and hexamethyl phosphoric acid triamide), dimethylsulfoxide, mercaptoacetic acid, acetic acid and pyridine.

Among the 1,2,4-triazine derivative (III) which is produced by themethod of the present invention, the following derivative (III′) is veryeffective for controlling parasitic protozoa.

wherein R² is acyl, optionally substituted sulfamoyl, optionallysubstituted carbanoyl, carboxyl, alkoxycarbonyl, optionally substitutedalkyl or optionally substituted amino and X′ is methylene or carbonyl.

The acyl means C₁₋₇ acyl such as formyl, acetyl, propionyl,isopropionyl, trifluoacetyl, and benzoyl. The optionally substitutedsulfamoyl means aminosulfonyl and C₁₋₅ sulfamoyl such asmethylaminosulfonyl, dimethylaminosulfonyl and morpholinosulfonyl. Theoptionally substituted carbamoyl means aminocarbonyl and C₁₋₇ carbamoylsuch as methylaminocarbonyl, dimethylaminocarbonyl, andphenylaminocarbonyl. The alkoxycarbonyl means C₁₋₇ alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl and phenoxycarbonyl. The optionallysubstituted alkyl means C₂₋₄ alkyl such as ethyl and isopropyl, andhalogeno-C₁₋₄ alkyl such as chloromethyl, 1-chloroethyl, 1-fluoroethyl,trifluoromethyl and trifluoroethyl, and hydroxy-C₁₋₄ alkyl such ashydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl, and C₁₋₄ alkoxy-C₁₋₄alkyl such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl,1-acetoxyethyl and 2-ethoxyethyl. The optionally substituted amino meansdi-C₁₋₄ alkyl amono such as dimethylamino and diethylamino.

Especially,2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one(Example No. 6) and2-{3,5-dichloro-4-[4-(1-hydroxyethyl)benzyl]phenyl}-4,5-dihydro-1,2,4-triazin-3(2H)-one(Example No. 16) are very useful, because these show high effectivenessfor controlling parasitic protozoa and have very low residue.

WORKING EXAMPLE Reference Example 1

Synthesis ofα-(3,4-dichlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)acetonitrile

To 150 ml of 20% hydrous DMSO were added 6.15 g of 3,4-dichlorobenzylcyanide, 8.13 g of 4-bromo-3,5-dichloronitrobenzene and 1.50 g of sodiumhydroxide. The reaction was allowed to proceed for one hour attemperatures ranging from 60 to 70° C. After completion of the reaction,DMSO was removed, and the residue was dissolved in 50 ml of toluene. Thesolution was washed with water, dried and concentrated. To theconcentrate was added ethyl alcohol to cause crystallization to affordthe titled compound in a yield of 67%, m.p.171-172° C.

¹H-NMR(CDCl₃); 6.21(s,1H), 7.13-7.52(m,3H), 8.29(s,2H).

Reference Example 2

Synthesis of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)aniline

In 100 ml of methanol were dissolved 7.6 g ofα-(3,4-dichlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)acetonitrile and0.8 g (50%) of Raney's nickel. The solution was subjected to reductionwith three times as much mol. of hydrogen gas. Insolubles were removedfrom the reaction mixture, then the remaining solution was concentratedto give the titled compound in a yield of 95%, m.p.191-194° C.

¹H-NMR(CDCl₃); 3.97(br,2H), 5.98(s,1H), 6.67(s,2H), 7.12-7.47(m,3H).

Reference Example 3

Synthesis of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)phenylhydrazine

In 40 ml of acetic acid was dissolved 3.0 g of3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)aniline. To the solution wasthen added 3 ml of 35% hydrochloric acid. To the mixture was addeddropwise, while cooling at temperatures ranging from 10 to 12° C., asolution of 0.8 g of 98.5% sodium nitrite in 3 ml of water. The reactionmixture was stirred for 40 minutes under the same conditions, to whichwas then added 7.0 g of stannous chloride dissolved in 10 ml of 35%hydrochloric acid. The reaction mixture was poured into ice-water, whichwas then made into alkaline, followed by extraction with 200 ml of ethylacetate. The extract was washed with water, dried over anhydrousmagnesium sulfate, and concentrated to afford the titled compound in ayield of 96%, m.p.183-185° C.

¹H-NMR(DMSO-d₆); 4.26(br,2H), 6.25(s,1H), 6.87(s,2H), 7.11-7.72(m,4H).

Reference Example 4

Synthesis of1-[3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)phenyl]-2-benzylidenehydrazineacetic acid ethyl ester

In 50 ml of acetic acid ethyl ester was dissolved 3.0 g of3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)phenylhydrazine. To thesolution was added equimol. of benzaldehyde, and the mixture was stirredfor 3 hours at room temperature. The reaction mixture was dried overanhydrous magnesium sulfate, which was then concentrated to afford thetitled compound in a yield of 68%, m.p.75-90° C.

¹H-NMR(CDCl₃); 1.25(t,3H), 2.04(s,3H), 4.12(q,2H), 6.03(s,1H),7.13(s,2H), 7.24-7.81(m,10H).

Reference Example 5

Synthesis of α-(4-chlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)methane

To 50 ml of 20% hydrous DMSO were added 1.9 g of 4-chlcrophenyl aceticacid methyl ester, 2.7 g of 4-bromo-3,5-dichloronitrobenzene and 0.5 gof sodium hydroxide. The reaction was allowed to proceed at temperaturesranging from 60 to 70° C. for one hour, then at temperatures rangingfrom 130 to 135° C. for 8 hours. After completion of the reaction, DMSOwas removed. The residue was dissolved in 50 ml of toluene. The solutionwas washed with water, dried and concentrated. To the concentrate wasadded ethyl alcohol to cause crystallization to afford the titledcompound in a yield of 91%, m.p.80-81° C.

¹H-NMR(CDCl₃); 4.36(s,2H), 7.17(q,4H), 8.20(s,2H).

Reference Example 6

Synthesis of α-(4-chlorophenyl)-α-(2,6-dichloro-4-aminophenyl)methane

In 30 ml of methanol were dissolved 1.6 g ofα-(4-chlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)methane and 0.2 g (50%)of Raney's hickel. The solution was subjected to reduction with threetimes as much mol. of hydrogen gas. Insolubles were removed and theremaining reaction mixture was concentrated to afford the titledcompound in a yield of 95%, m.p.141-142° C.

¹H-NMR(CDCl₃); 3.72(br,2H), 4.14(s,2H), 6.65(s,2H), 6.95-7.44(m,4H).

Reference Example 7

Synthesis ofα-(4-chlorophenyl)-α-(2,6-dichloro-4-hydrazinophenyl)methane

In 20 ml of acetic acid was dissolved 1.5 g ofα-(4-chlorophenyl)-α-(2,6-dichloro-4-aminophenyl)methane. To thesolution was then added 3 ml of 35% hydrochloric acid. To the mixturewas added dropwise, while cooling at temperatures ranging from 10 to 12°C., 0.4 g of 98.5% sodium nitrite dissolved in 1 ml of water. Thereaction mixture was stirred for 40 minutes under the same conditions,to which was then added 4.0 g of stannous chloride dissolved in 4 ml of35% hydrochloric acid. The reaction mixture was poured into ice-water,and the pH of the solution was made alkaline, followed by extractionwith 50 ml of acetic acid ethyl ester. The extract was washed withwater, dried over anhydrous magnesium sulfate, and concentrated toafford the titled compound in a yield of 95%, m.p.129-130° C.

¹H-NMR(CDCl₃); 3.57(br,2H), 4.17(s,2H), 5.23(br,1H), 6.83(s,2H),7.03-7.27(q,4H).

Reference Example 8

Synthesis of α-(4-chlorophenyl)-α-(2,6-dichloro-4-benzylidenehydrazinophenyl)methane

In 50 ml of dichloromethane was dissolved 0.7 g ofα-(4-chlorophenyl)-α-(2,6-dichloro-4-hydrazinophenyl)methane. To thesolution was added equimol. of benzaldehyde, and the mixture was stirredfor 3 hours at room temperature. The reaction mixture was dried overanhydrous magnesium sulfate, followed by concentration to afford thetitled compound in a yield of 98%, m.p.149-150° C.

¹H-NMR(CDCl₃); 4.20(s,2H), 7.09-7.68(m,13H).

Reference Example 9

Synthesis of benzaldehyde 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenylhydrazone

In 30 ml of acetic acid ethyl ester was dissolved 3.26 g of4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazine. To the solutionwas added equimolar benzaldehyde and three times as much mol. ofanhydrous magnesium sulfate, then the reaction was allowed to proceedfor one hour at room temperature. After completion of the reaction,insolubles were removed, and the solution was concentrated, which wasrecrystallized from acetonitrile to afford 3.3 g of the titled compoundas colorless crystals, m.p.162-163° C.

¹H-NMR(CDCl₃); 6.05(s,1H), 7.09(s,2H), 7.30(s,4H), 7.30-8.00(m,7H).

Reference Example 10

Synthesis of 4-(4-Acetylbenzyl)-3,5-dichloroaniline

In 11 ml of ethylacetate were dissolved 1.1 g4-(4-Acetylbenzyl)-3,5-dichloronitrobenzene and 3.8 g Tin (11) chloridedihydrate. The solution was allowed to proceed for one hour attemperatures ranging from 40-50° C. After completion of the reaction.The reaction mixture was poured into 100 ml ice-water, followed byextraction with 150 ml ethylacetate. The extract was washed with waterand 25% ammonia solution, dried over anhydrous magnesium sulfate, andconcentrated to afford the titled compound in a yield of 100%,m.p.97-98° C.

¹H-NMR(CDCl₃); 2.55(s,3H), 3.75(br,2H), 4.24(s,2H), 6.67(s,2H),7.25(d,2H), 7.85(d,2H).

Reference Example 11

Synthesis of2-[4-(4-Acetylbenzyl)-3,5-dichlorophenyl]-1-benzylidenehydrazine

In 10 ml of acetic acid was dissolved 1.0 g of4-(4-Acetylbenzyl)-3,5-dichloroaniline. To the solution was then added1.0 ml of 35% hydrochloric acid. To the mixture was added dropwise,while cooling at temperatures ranging from 8-10° C., a solution of 0.3 gof 98.5% sodium nitrite in 1.0 ml water. The reaction mixture wasstirred for one hour under the same conditions, to which was then added2.0 g of Tin (II) chloride dihydrate dissolved in 2.0 ml of 35%hydrochloric acid. The reaction mixture was stirred for 3 hours at roomtemperature. To the mixture then added 20 ml of water and 20 mlchloroform. To the mixture was added dropwise, while cooling at thetemperatures ranging from 5-10° C., 0.36 g of benzaldehyde. The reactionmixture was stirred for 30 minutes under the same conditions. Aftercompletion of the reaction, followed by extraction with 20 ml ofchloroform. The extract was washed with water and sturated sodiumhydrogen carbonate solution, dried over an hydrous magnesium sulfate,and concentrated to provide 0.88 g of the title compound as a colorlesscrystals, m.p.137-139° C.

¹H-NMR(CDCl₃); 2.56(s,3H), 4.29(s,2H), 7.11-7.90(m,13H).

Working Example 1

Synthesis of1-benzylidene-2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4-(2,2-diethoxyethyl)-semicarbazide

In 5 ml of acetonitrile was dissolved 0.5 g ofα-(4-chlorophenyl)-α-(2,6-dichloro-4-benzylidenehydrazinophenyl)methane.To the solution were added 0.3 g of 2,2-diethoxyethylisocyanate and0.015 g of DBU. The mixture was stirred for one hour at roomtemperature. The reaction mixture was cooled, then the resultingcrystalline precipitate was collected by filtration to give the titledcompound in a yield of 97%, m.p.138-139° C.

¹H-NMR(CDCl₃); 1.27(t,6H), 3.46-3.90(m,6H), 4.33(s,2H),6.92-7.63(m,13H).

Working Example 2

Synthesis of1-benzylidene-2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4-(2,2-dimethoxyethyl)semicarbazide

In 20 ml of acetonitrile was suspended 3.2 g of benzaldehyde4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazone. To thesuspension were added 1.5 g of 2,2-dimethoxyethyl isocyanate and 20 mgof DBU. The reaction was allowed to proceed for one hour at roomtemperature, then the resulting crystalline precipitate was collected byfiltration, which was washed with hexane, followed by drying to afford3.7 g of the titled compound as colorless crystals, m.p.190-191° C.

¹H-NMR(CDCl₃); 3.46(s,6H), 3.53(t,2H), 4.50(t,1H), 6.21(s,1H),6.80-7.10(m,1H), 7.20-7.70(m,12H).

Working Example 3

Synthesis of2-[4-(3-Acetylbenzyl)-3,5-dichlorophenyl]-1-benzylidene-4-(2,2-dimethoxyethyl)semicarbazide

In 8 ml of acetonitrile was dissolved 0.8 g of2-[4-(4-Acetylbenzyl)-3,5-dichlorophenyl]-1-benzylidenehydrazine. To thesolution were added 0.4 g 2,2-dimethoxyethylisocyanate and 0.015 g ofDBU. The mixture was stirred for one hour at room temperature. Thereaction mixture was poured into 30 ml ice-water, followed by extractionwith ethylacetate. The extract was washed with water, dried overanhydrous magnesium sulfate and concentrated. This residue was purifiedby column chromatography (Merck silica 60; hexane-ethylacetate=1:3) toprovide 0.73 g of the title compound as a light-yellow oil.

¹H-NMR(CDCl₃); 2.58(s,3H), 3.47(s,6H), 3.53(5,2H)), 4.15(5,1H),4.43(s,2H), 6.90-7.90(m,13H).

Working Example 4

Compounds produced by substantially the same manner as in WorkingExample 1-3 and their physical constants were set forth in Table 1.

TABLE 1 No. Compounds m.p. (° C.) ¹H-NMR [Solvent] δ 1

146˜147 [CDCl₃] 3.48(s, 6H) 3.55(t, 2H) 4.52(t, 1H) 6.94(t, 1H)7.15˜7.87(m, 12H) 2

162˜163 [CDCl₃] 3.45(s, 6H) 3.53(t, 2H) 4.51(t, 1H) 6.92(t, 1H)7.10˜7.70(m, 12H) 3

139˜140 [CDCl₃] 3.48(s, 6H) 3.55(t, 2H) 4.11(s, 2H) 4.53(t, 1H) 6.93(br,1H) 7.05˜7.70 (m, 13H) 4

119˜120 [CDCl₃] 3.43(s, 6H) 3.51(t, 2H) 4.48(t, 1H) 7.10˜7.75(m, 8H)7.80(s, 1H) 5

149˜150 [CDCl₃] 3.45(s, 6H) 3.52(t, 2H) 4.31(s, 2H) 4.49(t, 1H) 6.91(t,1H) 7.10˜7.75 (m, 12H) 6

190˜191 [CDCl₃] 3.32(dd, 2H) 3.48(s, 6H) 3.53(t, 1H) 4.50(t, 1H) 4.92(t,1H) 6.91(br, 1H) 7.15˜ 7.65(m, 12H) 7

caramel [CDCl₃] 1.71(s, 3H) 2.16(s, 3H) 3.41(s, 6H) 3.35˜3.47(m, 2H)4.22(s, 2H) 4.43(t, 1H) 5.98(br, 1H) 7.03˜7.27(q, 4H) 7.32(s, 2H) 8

140˜141 [CDCl₃] 1.27(t, 6H) 3.46˜ 3.90(m, 6H) 4.33(s, 2H) 4.64 (t, 1H)6.92˜7.63(m, 13H) 9

160˜162 [CDCl₃] 1.28(t, 6H) 3.46˜ 3.90(m, 6H) 4.63(t, 1H) 6.20 (s, 1H)6.99(t, 1H) 7.13˜7.68 (m, 11H) 10

caramel [CDCl₃] 2.21(s, 3H) 3.49˜ 3.62(m, 8H) 4.54(t, 1H) 6.92˜ 7.82(m,13H) 11

163˜164 [CDCl₃] 2.32(s, 3H) 3.47˜ 3.60(m, 8H) 4.02(s, 2H) 4.52 (t, 1H)6.83˜7.60(m, 13H) 12

178˜183 [CDCl₃] 3.39˜3.56(m, 2H) 3.47(s, 6H) 4.51(t, 1H) 6.20 (s, 1H)7.23˜7.67(m, 12H) 13

caramel [CDCl₃] 2.49(s, 3H) 2.43˜ 3.60(m, 8H) 4.54(t, 1H) 6.93˜ 7.58(m,9H) 14

caramel [DMSO-d₆] 2.50(s, 3H) 3.40˜ 3.66(m, 8H) 4.52(t, 1H) 6.18 (s, 1H)6.90˜7.73(m, 9H) 15

caramel [CDCl₃] 2.12(s, 3H) 3.43˜ 3.63(m, 2H) 3.49(s, 6H) 4.55 (t, 1H)6.91˜7.67(m, 13H) 16

caramel [CDCl₃] 2.21(s, 3H) 3.48˜ 3.61(m, 2H) 3.48(s, 6H) 4.54 (t, 1H)6.73˜7.60(m, 13H) 17

oil [CDCl₃] 1.18(t, 3H) 1.35(t, 3H) 3.45(s, 6H) 3.60(t, 2H) 3.85(q, 2H)4.40(t, 1H) 4.45 (q, 2H) 6.90˜7.60(m, 4H) 18

— — 19

oil [CDCl₃] 3.48(S, 6H) 3.66(t, 2H) 4.52(t, 1H) 6.95(t, 1H) 7.14(q, 4H)7.45(S, 2H) 7.20˜ 7.82(m, 6H) 20

194˜195 [CDCl₃] 2.35(S, 3H) 3.48(S, 6H) 3.52(t, 2H) 4.51(t, 1H) 6.22(S,1H) 6.92(br, 1H) 7.10˜7.90(m, 12H) 21

oil [CDCl₃] 2.58(s, 3H) 3.47(s, 6H) 3.53(m, 2H) 4.51(t, 1H) 4.43(s, 2H)6.90˜7.90 (m, 13H) 22

— — 23

161˜162 [CDCl₃] 3.47˜3.59(m, 8H) 4.51(t, 1H) 6.22(s, 1H) 6.90 (br, 1H)7.27˜7.66(m, 11H) 24

166˜168 [CDCl₃] 2.40(s, 3H) 3.47˜ 3.60(m, 8H) 4.52(t, 1H) 6.08 (s, 1H)6.93(t, 1H) 7.06˜7.64 (m, 11H) 25

144˜145 [DMSO-d₆] 2.27(s, 3H) 3.32 (s, 6H) 3.27˜3.66(m, 2H) 4.50(t, 1H)6.37(s, 1H) 7.36˜ 7.96(m, 12H) 26

185˜186 [CDCl₃] 3.98(s, 6H) 3.53(t, 2H) 3.91(s, 3H) 4.50(t, 1H) 6.24(s,1H) 6.65˜7.75 (m, 12H) 27

145˜146 [CDCl₃] 2.28(s, 3H) 3.48(s, 6H) 3.55(t, 2H) 4.51(t, 1H) 6.20(s,1H) 6.75˜7.80 (m, 12H) 28

184˜185 [CDCl₃] 3.48(s, 6H) 3.54(t, 2H) 4.51(t, 1H) 6.28(s, 1H) 6.95(br,1H) 7.20˜7.75 (m, 12H) 29

90˜92 [CDCl₃] 3.48(s, 6H) 3.39˜ 3.60(m, 2H) 4.50(t, 1H) 5.83 (s, 1H)6.85˜7.70(m, 13H) 30

90˜92 [CDCl₃] 2.16(s, 3H) 3.53˜ 3.82(m, 8H) 4.52(t, 1H) 6.28 (s, 1H)6.80˜7.67(m, 12H) 31

77˜78 [CDCl₃] 3.48(s, 6H) 3.51˜ 3.64(m, 2H) 4.49(t, 1H) 7.13˜ 7.93(m,14H) 32

62˜63 [CDCl₃] 2.44(s, 3H) 3.40˜ 3.61(m, 8H) 4.57(t, 1H) 6.90˜ 7.80(m,14H) 33

oil [CDCl₃] 3.48(s, 6H) 3.54(t, 2H) 4.51(t, 1H) 4.57(s, 2H) 6.92(br, 1H)7.20˜7.70 (m, 8H) 34

133˜134 [CDCl₃] 3.47˜3.58(m, 8H) 4.33(s, 2H) 4.51(t, 1H) 6.91 (t, 1H)7.19˜7.63(m, 10H) 8.37(d, 1H) 35

146˜147 [CDCl₃] 3.30˜3.68(m, 8H) 4.51(t, 1H) 6.30(s, 1H) 6.95 (br, 1H)7.10˜7.85(m, 12H) 36

188˜190 [CDCl₃] 3.40˜3.70(m, 8H) 4.51(t, 1H) 6.31(s, 1H) 6.98 (br, 1H)7.20˜7.90(m, 12H) 37

resinous [DMSO-d₆] 2.46(s, 3H) 3.19˜ 3.43(m, 8H) 4.56(t, 1H) 6.46 (s,1H) 7.29˜7.89(m, 10H) 8.31(d, 1H) 38

— — 39

132˜134 [CDCl₃] 3.47˜3.58(m, 8H) 4.33(s, 2H) 4.51(t, 1H) 6.91 (t, 1H)7.19˜7.63(m, 10H) 8.37(d, 1H) 40

oil [CDCl₃] 3.47˜3.56(m, 8H) 4.50(t, 1H) 6.25(s, 1H) 6.79˜ 6.97(m, 2H)7.30˜7.58 (m, 9H) 41

199˜201 [CDCl₃] 2.30(s, 3H) 3.47˜ 3.60(m, 8H) 4.52(t, 1H) 6.15 (s, 1H)6.93(t, 1H) 7.04˜ 7.66(m, 12H) 42

caramel [CDCl₃] 2.17(s, 3H) 3.33˜ 3.68(m, 4H) 3.48(s, 6H) 4.52 (t, 1H)6.49(s, 1H) 6.94(t, 1H) 7.17˜7.60(m, 12H) 43

149˜151 [CDCl₃] 1.96(s, 3H) 3.48˜ 3.60(m, 8H) 3.72(q, 2H) 4.52 (t, 1H)6.09(s, 1H) 6.94(t, 1H) 7.19˜7.65(m, 12H) 44

121˜122 [CDCl₃] 1.22(t, 3H) 2.97(q, 2H) 3.47˜3.59(m, 8H) 4.42˜ 4.58(m,3H) 6.91˜7.94 (m, 13H) 45

caramel [CDCl₃] 1.21(d, 6H) 3.47˜ 3.60(m, 8H) 4.12(m, 1H) 4.43 (s, 2H)4.52(t, 1H) 6.91(t, 1H) 7.25˜7.94(m, 12H) 46

158˜160 [CDCl₃] 3.47˜3.60(m, 8H) 4.46(s, 2H) 4.52(t, 1H) 6.92(t, 1H)7.29˜7.80(m, 16H)

Working Example 5

Synthesis of2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one

In 5 ml of acetonitrile was dissolved 0.4 g of1-benzylidene-2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4-(2,2-diethoxyethyl)-semicarbazide.To the solution was added one drop of 35% hydrochloric acid. The mixturewas stirred for one hour at room temperature. The reaction mixture wascooled, then resulting crystalline precipitate of the titled compoundwas collected by filtration. The yield was 95%. m.p.199-200° C.

¹H-NMR(CDCl₃); 4.05(t,2H), 4.25(s,2H), 6.50(br,1H), 7.05(t,1H),7.19(s,4H), 7.60(s,2H).

Working Example 6

Synthesis of2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one

In 7 ml of ethyl acetate was dissolved 0.7 g of2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-1-benzylidene-4-(2,2-dimethoxyethyl)semicarbazide.To the solution was added 0.27 g of 35% hydrochloric acid. The mixturewas stirred for one hour at room temperature. The reaction mixture waswashed with water, dried and concentrated. The residue was purified bycolumn chromatography (Merck Silica Gel 60;normalhexane-ethylacetate=1:3) to provide 0.24 g of the title compound.m.p.189-190° C.

¹H-NMR(CDCl₃); 2.56(s.3H), 4.14(5,2H), 4.35(s,2H), 5.60(br,1H),7.11(m,1H), 7.28(d,2H), 7.62(s,2H), 7.85(d,2H).

Working Example 7

Compounds produced by substantially the same manner as in WorkingExample 5 and their physical constants were set forth in Table 2.

TABLE 2 No. Compounds m.p. (° C.) ¹H-NMR [Solvent] δ  1

109˜110 [CDCl₃] 4.15(t, 2H) 6.52(br, 1H) 7.10(q, 4H) 7.23(br, 1H)7.86(s, 2H)  2

222˜223 [CDCl₃] 4.14(m, 2H) 4.28(s, 2H) 5.85(br, 1H) 7.00˜7.30(m, 5H)7.50(d, 1H)  3

210˜211 [CDCl₃] 2.38(s, 3H) 4.10˜4.13 (m, 2H) 5.92(br, 1H) 6.02(s, 1H)7.11˜7.61(m, 6H)  4

221˜222 [CDCl₃] 4.12˜4.17(m, 2H) 5.67 (br, 1H) 6.14(s, 1H) 7.12˜7.57(m,4H) 7.73(s, 2H)  5

215˜216 [CDCl₃] 2.30(s, 3H) 4.16(m, 2H) 5.80(br, 1H) 6.23(s, 1H)7.06˜7.46 (m, 6H)  6

197˜198 [CDCl₃] 3.99(m, 2H) 6.40˜6.76 (m, 2H) 6.92˜7.33(m, 6H) 7.63(s,2H)  7

146˜147 [CDCl₃] 4.07(s, 2H) 4.14(m, 2H) 6.04(br, 1H) 6.88˜7.36(m, 7H)  8

97˜99 [CDCl₃] 4.08˜4.19(m, 2H) 5.75 (s, 1H) 5.95(s, 1H) 7.15˜7.39 (m,5H) 8.00(m, 2H)  9

212˜213 [CDCl₃] 2.33(s, 3H) 4.10(m, 2H) 6.12(s, 1H) 6.34(br, 1H) 7.11(t,1H) 7.19(s, 4H) 7.70(s, 2H) 10

213˜214 [CDCl₃] 2.28(s, 3H) 4.14(m, 2H) 5.76 (s, 1H) 5.98(s, 1H)7.12˜7.37(m, 4H) 7.74(s, 2H) 11

220˜221 [CDCl₃] 2.56(s, 3H) 4.17(m, 2H) 5.40(br, 1H) 6.90(d, 2H) 7.14(m,1H) 7.69(s, 2H) 7.93(d, 2H) 12

189˜190 [CDCl₃] 2.56(s, 3H) 4.14(m, 2H) 4.35(s, 2H) 5.60(br, 1H) 7.11(m,1H) 7.28(d, 2H) 7.62(s, 2H) 7.85(d, 2H) 13

205˜206 [CDCl₃] 4.01(t, 2H) 4.24(s, 2H) 6.98(s, 1H) 6.90˜7.45(m, 4H)8.30(s, 1H) 14

161˜162 [CDCl₃] 3.28(s, 3H) 4.12˜4.17(m, 2H) 4.44(q, 2H) 5.55(br, 1H)6.00(s, 1H) 7.09˜7.17(m, 1H) 7.28(q, 4H) 7.64(d, 1H) 7.70(d, 1H) 15

170˜171 [CDCl₃] 4.13˜4.18(m, 2H) 5.64(br, 1H) 6.15(s, 1H) 7.13˜7.21(m,1H) 7.33(d, 1H) 7.67(ddd, 1H) 7.77(S, 2H) 8.40(dd, 1H) 16

187˜188 [CDCl₃] 4.11˜4.16(m, 2H) 4.25(s, 2H) 5.66(br, 1H) 7.07˜7.14(m,1H) 7.19(d, 1H) 7.46(dd, 1H) 7.62(s, 2H) 8.32(dd, 1H) 17

211˜212 [CDCl₃] 3.85(s, 3H) 4.02(m, 2H) 6.40(s, 1H) 6.79(d, 1H) 7.04(br,1H) 7.39(br, 1H) 7.46(d, 1H) 7.79(s, 3H) 18

185˜186 [CDCl₃] 2.23(d, 3H) 4.09(m, 2H) 6.10(s, 1H) 6.54(br, 1H)6.75˜7.30 (m, 4H) 7.70(s, 2H) 19

174˜175 [CDCl₃] 4.10(m, 2H) 6.18(s, 1H) 6.55(br, 1H) 7.13(t, 1H) 7.30(s,4H) 7.74(d, 1H) 7.91(d, 1H) 20

217˜218 [CDCl₃] 4.01(t, 2H) 6.48(s, 1H) 7.00˜7.90(m, 6H) 7.85(s, 2H) 21

220˜221 [DMSO-d₆] 4.02(t, 2H) 6.36(s, 1H) 7.19˜7.87(m, 7H) 8.28(s, 1H)22

211˜212 [CDCl₃] 2.26(s, 3H) 4.10(t, 2H) 6.06(s, 1H) 7.00˜7.70(m, 8H) 23

caramel [CDCl₃] 2.16(s, 6H) 3.44(q, 2H) 4.12˜4.17(m, 2H) 5.41(br, 1H)6.44(s, 1H) 7.08˜7.36(m, 5H) 7.53(d, 1H) 7.64(d, 1H) 24

caramel [CDCl₃] 1.96(s, 3H) 3.71(q, 2H) 4.13˜4.16(m, 2H) 5.88(br, 1H)6.01(s, 1H) 7.10˜7.39(m, 5H) 7.66(s, 2H) 25

186˜187 [DMSO-d₆] 3.96˜4.01(m, 2H) 4.25 (s, 2H) 7.29˜7.75(m, 3H) 7.65(s,2H) 8.26(d, 1H) 9.39(br, 2H) 26

171˜172 [CDCl₃] 4.13(m, 2H) 6.03(br, 1H) 6.17(d, 1H) 6.78(d, 1H)6.94(dd, 1H) 7.15(t, 1H) 7.74(s, 2H) 27

187˜188 [CDCl₃] 1.20(t, 3H) 2.95(q, 2H) 4.11˜4.16(m, 2H) 4.35(s, 2H)5.50(br, 1H) 7.07˜7.31(m, 3H) 7.62(s, 2H) 7.85(d, 2H) 28

150˜151 [CDCl₃] 1.19(d, 6H) 3.51(m, 1H) 4.35(s, 2H) 5.75(br, 1H)7.07˜7.15(m, 1H) 7.27(d, 2H) 7.62(d, 2H) 7.85(d, 2H) 29

205˜206 [CDCl₃] 4.11˜4.16(m, 2H) 4.38(s, 2H) 5.67(br, 1H) 7.05˜7.15(m,1H) 7.25˜7.78(m, 10H)

Working Example 8

Synthesis of2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione

In 2 ml of acetic acid were dissolved 0.2 g of2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-4,5-dihydro-1,2,4-triazine-3(2H)-oneand 0.2 ml of hydrogenperoxide (30%). The reaction was allowed toproceed for 3 hours at temperatures ranging from 100 to 110° C. To thereaction mixture was added 20 ml of water to cause precipitation of thetitled compound as crystalline product. The product was collected byfiltration. The yield was 85%. m.p.175-176° C.

¹H-NMR(DMSO-d₆); 4.30(s,2H), 7.25(q,4H), 7.70(s,1H), 7.74(s,2H),12.46(br,1H).

Working Example 9

Compounds produced by substantially the same manner as in WorkingExample 8 and their physical constants were set forth in Table 3.

TABLE 3 No. Compounds m.p. (° C.) ¹H-NMR [Solvent] δ 1

183˜184 [CDCl₃] 2.57(s, 3H) 4.40(s, 2H) 7.27(d, 2H) 7.59(s, 1H) 7.66(s,2H) 7.88(d, 2H) 9.35(br, 1H) 2

224˜225 [CDCl₃] 4.33(s, 2H) 7.19(q, 4H) 7.45(d, 1H) 7.56(s, 1H) 9.10(br,1H) 3

234˜235 [DMSO-d₆] 7.27(q, 4H) 7.78(s, 1H) 8.03(s, 2H) 12.60(s, 1H) 4

294˜295 [DMSO-d₆] 6.49(br, 2H) 7.28(q, 4H) 7.71(s, 1H) 7.80(s, 2H)12.50(s, 1H) 5

172˜173 [DMSO-d₆] 7.25(q, 4H) 7.72(s, 1H) 7.88(s, 2H) 12.50(s, 1H) 6

175˜176 [DMSO-d₆] 4.28(s, 2H) 7.25(q, 4H) 7.69(s, 1H) 7.73(s, 2H)12.50(br, 1H) 7

106˜107 [DMSO-d₆] 7.28(d, 1H) 7.39(q, 4H) 7.72(s, 1H) 7.80(s, 2H)12.50(br, 1H) 8

161˜162 [CDCl₃] 2.26(d, 3H) 7.19(d, 1H) 7.14˜7.59(m, 7H) 8.95(br, 1H) 9

221˜222 [DMSO-d₆] 2.18(s, 3H) 7.75(q, 4H) 7.89(s, 2H) 12.40(br, 1H) 10 

261˜262 [CDCl₃] 2.32(s, 3H) 6.11(s, 1H) 7.17˜7.42(m, 5H) 7.60(s, 1H)7.66(d, 1H) 11 

178˜179 [CDCl₃] 4.31(s, 2H) 7.26(s, 1H) 7.48 (dd, 1H) 7.63(d, 1H)7.67(s, 2H) 8.33 (d, 1H) 8.78(br, 1H)

Working Example 10

Production of2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one

In 30 ml of acetonitrile was suspended 3.5 g of1-benzylidene-2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4-(2,2-dimethoxyethyl)semicarbazideproduced in Working Example 2. To the suspension was added 0.7 g of 35%hydrochloric acid, and the reaction was allowed to proceed for one hourat room temperature. After completion of the reaction, the reactionmixture was cooled for 30 minutes at temperatures ranging from 0 to 10°C., then resulting crystalline precipitate was collected by filtrationto afford 2.3 g of the titled compound as colorless crystals,m.p.166-167° C.

¹H-NMR(CDCl₃); 4.09(t,2H), 6.11(s,1H), 6.52(br,1H), 7.12(t,1H),7.30(s,4H), 7.70(s,2H).

Working Example 11

Production of2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dione

In 20 ml of acetic acid was dissolved 2.0 g of2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one.To the solution was added three times as much mol. of 30% hydrogenperoxide. The reaction was allowed to proceed for 3 hours at 100° C.After completion of the reaction, the reaction mixture was poured intoice-water. Resulting crystalline precipitate was collected by filtrationto afford 1.8 g of the titled compound as colorless crystals,m.p.290-292° C.

¹H-NMR(DMSO-d₆); 6.53(s,1H), 7.40(q,4H), 7.72(s,1H), 7.85(s,2H),12.50(s,1H).

Working Example 12

Synthesis of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-1,2,4-triazine-3(2H)-oxo-5(4H)-thione

In 50 ml of toluene was suspended 1.9 g of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dione.To the suspension was added 1.2 g of2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide andrefluxed for one hour. After completion of the reaction, insolubles wereremoved and the solution was concentrated. After the concentrate wasadded diethylether, 1.8 g of the title compound was filtlated ascrystals. m.p.173-175° C.

Working Example 13

Compounds produced by substantially the same manner as in WorkingExample 12 and their physical constants were set forth in Table 4.

TABLE 4 No. Compounds m.p. (° C.) ¹H-NMR [Solvent] δ 1

173˜175 [DMSO-d₆] 4.29(s, 2H) 7.25(q, 4H) 7.79(s, 2H) 7.89(s, 1H)13.90(br, 1H) 2

104˜106 [DMSO-d₆] 2.16(s, 3H) 7.60˜7.89(s, 7H) 13.89(br, 1H) 3

234˜235 [DMSO-d₆] 2.41(s, 3H) 6.36(s, 1H) 7.17˜7.70(m, 6H) 7.87(s, 1H)13.36(br, 1H) 4

249˜250 [DMSO-d₆] 6.25(s, 1H) 7.41(q, 4H) 7.88(s, 1H) 7.90(s, 2H)13.90(br, 1H)

Working Example 14

Synthesis of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-hexahydro-1,2,4-triazine-3,5(3H,4H)-dione

In 100 ml of acetic acid was dissolved 2.3 g of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dioneand refluxed with 3.1 g zinc powder for 3 hours. After completion of thereaction, insolubles were removed, and the solution was concentrated.After concentrating was added 20 ml iced water, then the resultingcrystalline precipitate was collected by filtration, which was washedwith methanol, followed by drying to afford 2.1 g of the title compoundas colorless crystals, m.p.267-268° C.

Working Example 15

Compounds produced by substantially the same manner as in WorkingExample 14 and their physical constants were set forth in Table 5.

TABLE 5 No. Compounds m.p. (° C.) ¹H-NMR [Solvent] δ 1

267˜268 [DMSO-d₆] 3.70(d, 2H) 4.20(s, 2H) 6.50(t, 1H) 7.23(q, 4H)7.85(s, 1H) 10.80(s, 1H) 2

270˜271 [DMSO-d₆] 3.72(d, 1H) 6.52(t, 2H) 7.20(q, 4H) 8.03(s, 2H)10.90(s, 1H) 3

215˜216 [DMSO-d₆] 4.00(d, 2H) 6.42(s, 1H) 6.64(t, 1H) 7.35(q, 4H)7.95(s, 2H) 12.50(s, 1H) 4

217˜218 [DMSO-d₆] 2.34(s, 3H) 3.99(d, 2H) 6.26(s, 1H) 6.62(s, 1H)7.14˜7.53 (m, 4H) 7.63(d, 1H) 7.77(d, 1H) 12.41(s, 1H) 5

caramel [CDCl₃] 2.26(s, 3H) 3.81(d, 2H) 4.87(t, 1H) 6.05(s, 1H)7.14˜7.39 (m, 4H) 7.59(d, 1H) 7.81(d, 1H) 8.34(s, 1H)

Working Example 16

Synthesis of2-{4-[4-(1-hydroxyethyl)benzyl]-3,5-dichlorophenyl}-4,5-dihydro-1,2,4-triazin-3(2H)-one

In 1.5 ml of ethanol was suspended 0.15 g of2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-4,5-dihydra-1,2,4-triazin-3(2H)-one.To the suspension was added 0.1 g of sodium borohydride. The mixture wasstirred for one hour at room temperature. The reaction mixture waspoured into 10 ml ice-water, followed by extraction with 10 ml ofethylacetate. The extract was dried over anhydrous magnesium sulfate,and concentrated. This residue was purified by column chromatography(Merck Silica Gel 60; hexane-acetone=1:1) to provide 0.13 g of the titlecompound as colorless crystals, m.p.119-120° C.

¹H-NMR(CDCl₃); 1.52(d,3H), 2.58(br,1H), 4.12(m,2H), 4.29(s,2H),4.81-4.96(m,1H), 5.29(br,1H), 7.05-7.33(m,5H), 7.59(s,2H).

Working Example 17

Synthesis of2-{4-[4-(1-hydroxypropyl)benzyl]-3,5-dichlorophenyl}-4,5-dihydro-1,2,4-triazin-3(2H)-one

The title compound was synthesized in otherwise a similar manner asExample 16, m.p.148-149° C.

¹H-MMR(CDCl₃); 0.89(t,3H), 1.57-1.84(m,2H), 2.56(br,1H), 4.11(m,2H),4.29(s,2H), 4.54(m,1H), 5.56(br,1H), 7.05-7.20(n,5H), 7.59(s,2H).

Working Example 18

Synthesis of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dione

In 30 ml of tetrahydrofuran was dissolved 2.6 g of2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4,5-dihydra-1,2,4-triazin-3(2H)-one.To the solution was added 4.5 g of pyridinium chlorochromate. Themixture was stirred at room temperature overnight, after which theinsoluble matter was filtered off. The filtrate was concentrated. Theresidue was purified by column chromatography (Merck Silica Gel 60;chloroform-ethanol=20:1) to provide 2.2 g of the title compound ascolorless crystals, m.p.175-176° C.

The production method of this second embodiment is to produce various2-substituted-1,2,4-triazin-3-one derivatives, which are useful as, forexample, herbicides and agents of controlling parasitic pest,conveniently and in a high yield. These useful compounds have come to beproduced on an industrial scale, which makes a great contribution to theintroduction of triazine derivatives, which are useful as, for example,medicine, veterinary drugs and agricultural chemicals, into market lessexpensively. Besides, the second embodiment contributes a great deal tothe creation and development of useful and novel2-substituted-1,2,4-triazin-3-one derivatives.

What is claimed is:
 1. A compound or a salt thereof wherein saidcompound has a structure of the formula:

wherein ring A is an aromatic group which may be substituted with 1 to 5substituents selected from the group consisting of (1) C₁₋₄ alkyl, (2)C₂₋₄ alkenyl, (3) C₂₋₄ alkynyl, (4) C₃₋₅ cycloalkyl, (5) C₅₋₇cycloalkenyl, (6) C₇₋₁₁ aralkyl, (7) phenyl, (8) C₁₋₆ alkoxy, (9)phenoxy, (10) C₁₋₆ alkanoyl, (11) benzoyl, (12) C₁₋₆ alkanoyloxy, (13)carboxyl, (14) C₂₋₇ alkoxycarbonyl, (15) carbamoyl, (16) N-mono-C₁₋₆alkylcarbamoyl, (17) N-di-C₁₋₄ alkylcarbamoyl, (18) cycloaminocarbonyl,(19) halogen, (20) mono-, di- or tri-halo-C₁₋₄ alkyl, (21) oxo, (22)amidino, (23) imino, (24) amino which may be protected with a groupselected from (i) formyl, (ii) C₁₋₆ alkyl-carbonyl which may besubstituted with halogen atoms, (iii) C₆₋₁₀ aryl-carbonyl which may besubstituted with 1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitrogroup, (iv) C₁₋₆ alkyloxycarbonyl which may be substituted with 1 to 3halogen atoms, C₁₋₆ alkylcarbonyl or nitro group, (v) C₆₋₁₀aryloxycarbonyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (vi) C₇₋₁₂ aralkyl-carbonyl which may besubstituted with 1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitrogroup, (vii) trityl which may be substituted with 1 to 3 halogen atoms,C₁₋₆ alkylcarbonyl or nitro group and (viii) phthaloyl which may besubstituted with 1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitrogroup, (25) mono-C₁₋₄ alkylamino, (26) di-C₁₋₄ alkylamino, (27) 3- to6-membered cycloamino which may contain 1 to 3 hetero atoms selectedfrom oxygen, sulfur and nitrogen, (28) C₁₋₆ alkanamido, (29) benzamido,(30) carbamoylamino, (31) N—C₁₋₄ alkylcarbamoylamino, (32) N,N-di-C₁₋₄alkylcarbamoylamino, (33) C₁₋₃ alkylenedioxy, (34) —B(OH)₂, (35)hydroxy, (36) epoxy, (37) nitro, (38) cyano, (39) mercapto, (40) sulfo,(41) sulfino, (42) phosphono, (43) dihydroxypolyol, (44) sulfamoyl, (45)mono-C₁₋₆ alkylsulfamoyl, (46) di-C₁₋₄ alkylsulfamoyl, (47) C₁₋₆alkylthio, (48) phenylthio, (49) C₁₋₆ alkylsulfinyl, (50)phenylsulfinyl, (51) C₁₋₆ alkylsulfonyl, (52) phenylsulfonyl and (53) 5-or 6-membered heterocyclic group containing 1 to 4 hetero atoms selectedfrom oxygen, sulfur and nitrogen, which may bound through one or twoatomic chain containing oxygen, sulfur, nitrogen and carbon, in whichany group having a carbon chain of 2 or more carbon atoms or a cyclicgroup may be further substituted with one or two substituents selectedfrom the group consisting of (a) halogen, (b) hydroxy, (c) oxo, (d) C₁₋₄alkoxy, (e) di-C₁₋₄ alkylamino, (f) halo-C₁₋₄ alkyl, (g) C₁₋₄ acyl, (h)hydroxy-C₁₋₄ alkyl, (i) C₁₋₄ alkoxy-C₁₋₄ alkyl, (j) cyano, (k) thioxoand (l) C₁₋₄ alkylthio, and in which when the substituent mentionedabove exists on two ring-forming atoms adjacent to each other, they maybind together to form a ring: X is oxygen or sulfur; R¹ is hydrogen,C₁₋₇ acyl, C₁₋₇ alkyloxycarbonyl, C₁₋₄ alkyl, mono-, di- or trihalo-C₁₋₄alkyl, or C₁₋₄ alkylcarbonyl; R² and R³ are independently selected fromthe group consisting of a hydrogen atom, a halogen atom, cyano, carboxy,carbamoyl, mercapto, hydroxy, C₁₋₄ alkyl, C₁₋₆ alkylthio, C₇₋₁₁aralkylthio, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl and a 5- to 7-membered heterocyclic group containing one tofour hetero-atoms selected from group consisting of nitrogen, sulfur andoxygen, wherein the alkyl, alkylthio, aralkylthio, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl or heterocyclic group may have one or twosubstituents selected from the group consisting of (a) halogen, (b)hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e) di-C₁₋₄ alkylamino, (f) halo-C₁₋₄alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄ alkyl, (i) C₁₋₄ alkoxy-C₁₋₄alkyl, (j) thioxo, (k) sulfide, (l) C₃₋₆ cycloalkyl and (m) mercapto, orwhen taken together, R² and R³ represent ═S; R⁴ and R⁵ are independentlyselected from the group consisting of a hydrogen atom, a halogen atom,cyano, carboxy, carbamoyl, amino, nitro, hydroxy, mercapto, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl and a 5- to7-membered heterocyclic group containing one to four hetero-atomsselected from the group consisting of nitrogen, sulfur and oxygen,wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclicgroup may have one or two substituent groups selected from the groupconsisting of (a) halogen, (b) hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e)di-C₁₋₄ alkylamino, (f) halo-C₁₋₄ alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄alkyl and (i) C₁₋₄ alkoxy-C₁₋₄ alkyl; R⁶ is selected from the groupconsisting of (1) a hydrogen atom, (2) a hydrocarbon residue selectedfrom the group consisting of C₁₋₁₅ alkyl, C₃₋₈ cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl and C₇₋₁₆aralkyl, each of which may have one to five substituent groups selectedfrom the group consisting of (1) nitro, (2) hydroxy, (3) oxo, (4)thioxo, (5) cyano, (6) carbamoyl, (7) carboxyl, (8) C₁₋₄ alkoxycarbonyl,(9) sulfo, (10) halogen, (11) C₁₋₄ alkoxy, (12) phenoxy, (13)halophenoxy, (14) C₁₋₄ alkylthio, (15) phenylthio, (16) C₁₋₄alkylsulfinyl, (17) C₁₋₄ alkylsulfonyl, (18) amino, (19) C₁₋₆ acylamino,(20) mono- or di-C₁₋₄ alkylamino, (21) C₁₋₄ acyl, (22) benzoyl, (23) 5-or 6-membered heterocyclic group containing one to four hetero-atomsselected from the group consisting of oxygen, sulfur and nitrogen, whichmay be substituted by one to four substituents selected from the groupconsisting of (a) halogen, (b) C₁₋₄ alkyl and (c) halophenoxy, and (24)C₁₋₁₀ haloalkyl, and where the hydrocarbon group is cycloalkyl,cycloalkenyl, aryl or aralkyl, each of which may have one to four C₁₋₄alkyl group, (3) an acyl group selected from the group consisting of—COR^(a), —CONHR^(a), —CSR^(a) and —CSNHR^(a) wherein R^(a) representshydrogen or a hydrocarbon group selected from the group consisting ofC₁₋₁₅ alkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkenyl, C₆₋₁₄ aryl and C₇₋₁₆ aralkyl, wherein each hydrocarbongroup may be substituted with one or two substituent groups selectedfrom the group consisting of (1) nitro, (2) hydroxy, (3) oxo, (4)thioxo, (5) cyano, (6) carbamoyl, (7) carboxyl, (8) C₁₋₄ alkoxycarbonyl,(9) sulfo, (10) halogen, (11) C₁₋₄ alkoxy, (12) phenoxy, (13)halophenoxy, (14) C₁₋₄ alkylthio, (15) phenylthio, (16) C₁₋₄alkylsulfinyl, (17) C₁₋₄ alkylsulfonyl, (18) amino, (19) C₁₋₆ acylamino,(20) mono- or di-C₁₋₄ alkylamino, (21) C₁₋₄ acylt (22) benzoyl, and (23)5- or 6-membered heterocyclic group containing one to four hetero-atomsselected from the group consisting of oxygen, sulfur and nitrogen, whichmay be substituted by one to four substituents selected from the groupconsisting of (a) halogen, (b) C₁₋₄ alkyl and (c) halophenoxy, and whenthe hydrocarbon group is cycloalkyl, cycloalkenyl, aryl or aralkyl, eachmay have one to four C₁₋₄ alkyl groups, (4) an oxycarbonyl group of theformula —COOR^(a) wherein R^(a) is as defined above, and (5) a 5- to8-membered heterocyclic group or condensed heterocyclic group derivedtherefrom containing one to four hetero-atoms selected from the groupconsisting of oxygen sulfur and nitrogen, which may have one to fivesubstituent groups selected from the group consisting of (1) C₁₋₄ alkyl,(2) C₂₋₄ alkeyl, (3) C₂₋₄ alkynyl, (4) C₃₋₆ cycloalkyl, (5) C₅₋₇cycloalkenyl, (6) C₇₋₁₁ aralkyl, (7) phenyl, (8) C₁₋₆ alkoxy, (9)phenoxy, (10) C₁₋₆ alkanoyl, (11) benzoyl, (12) C₁₋₆ alkanoyloxy, (13)carboxyl, (14) C₂₋₇ alkoxycarbonyl, (15) carbamoyl (16) N-mono-C₁₋₄alkylcarbamoyl, (17) N,N-di-C₁₋₄ alkylcarbamoyl, (18)cycloaminocarbonyl, (19) halogen, (20) mono-, di- or trihalo-C₁₋₄ alkyl,(21) oxo, (22) amidino, (23) imino, (24) amino, (25) mono-C₁₋₄alkylamino, (26) di-C₁₋₄ alkylamino, (27) 3- to 6-membered cycloaminocontaining 1 to 3 hetero-atoms selected from oxygen, sulfur, andnitrogen, (28) C₁₋₆ alkanoylamido, (29) benzamido, (30) carbamoylamino,(31) N—C₁₋₄ alkylcarbamoylamino, (32) N,N-di-C₁₋₄ alkylcarbamoylamino,(33) C₁₋₃ alkylenedioxy, (34) —B(OH)₂, (35) hydroxy, (36) epoxy, (37)nitro, (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42)phosphono, (43) dihydroxypolyol, (44) sulfamoyl, (45) mono-C₁₋₆alkylsulfamoyl (46) di-C₁₋₄ alkylsulfamoyl, (47) C₁₋₆ alkylthio (48)phenylthio, (49) C₁₋₆ alkylsulfinyl, (50) phenylsulfinyl, (51) C₁₋₆alkylsulfonyl and (52) phenylsulfonyl, and wherein the hydrocarbongroup, 5- to 8-membered heterocyclic group and condensed heterocyclicgroup may be bound through a hetero-atom selected from the groupconsisting of a nitrogen atom of an amino, C₁₋₄ alkylamino, hydroxyaminoor hydrazino group, a sulfur atom of a thiocarbonyl or sulfino group andan oxygen atom, R¹ and R² or R⁵ and R⁶ when taken together can form achemical bond; provided that where ring A is a phenyl group having atleast a halogen atom in position 2 or 4 and X is an oxygen atom, then R⁵and R⁶ do not bind together to form a chemical bond.
 2. A compound or asalt thereof as claimed in claim 1, wherein ring A is a phenyl groupwhich may be substituted with 1 to 5 substituents selected from thegroup consisting of (1) C₁₋₄ alkyl, (2) C₂₋₄ alkenyl, (3) C₁₋₄ alkynyl,(4) C₃₋₆ cycloalkyl, (5) C₅₋₇ cycloalkenyl, (6) C₇₋₁₁ aralkyl, (7)phenyl, (8) C₁₋₆ alkoxy, (9) phenoxy, (10) C₁₋₆ alkanoyl, (11) benzoyl,(12) C₁₋₆ alkanoyloxy, (13) carboxyl, (14) C₂₋₇ alkoxycarbonyl, (15)carbamoyl, (16) N-mono-C₁₋₄ alkylcarbamoyl, (17) N-di-C₁₋₄alkylcarbamoyl (18) cycloaminocarbonyl, (19) halogen, (20) mono-, di- ortri-halo-C₁₋₄ alkyl, (21) oxo, (22) amidino, (23) imino, (24) aminowhich may be protected with a group selected from (i) formyl, (ii) C₁₋₆alkyl-carbonyl which may be substituted with halogen atoms, (iii) C₆₋₁₀aryl-carbonyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (iv) C₁₋₆ alkyloxycarbonyl which may besubstituted with 1 to 3 halogen atoms, C₁₋₆ alkyloxycarbonyl which maybe substituted with 1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitrogroup, (v) C₆₋₁₀ aryloxycarbonyl which may be substituted with 1 to 3haloaen atoms, C₁₋₆ alkylcarbonyl or nitro group, (vi) C₇₋₁₂aralkylcarbonyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (vii) trityl which may be substituted with1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitro group and (viii)phthaloyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (25) mon-C₁₋₄ alkylamino, (26) di-C₁₋₄alkylamino, (27) 3- to 6-membered cycloamino which may contain 1 to 3hetero atoms selected from oxygen, sulfur and nitrogen, (28) C₁₋₆alkanamido, (29) benzamido, (30) carbamoylamino, (31) N—C₁₋₄alkylcarbamoylamino, (32) N,N-di-C₁₋₄ alkylcarbamoylamino, (33) C₁₋₃alkylenedioxy, (34) —B(OH)₂, (35) hydroxy, (36) epoxy, (37) nitro, (38)cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43)dihydroxypolyol, (44) sulfamoyl, (45) mono-C₁₋₆ alkylsulfamoyl, (46)di-C₁₋₄ alkylsulfamoyl, (47) C₁₋₆ alkylthio, (48) phenylthio, (49) C₁₋₆alkylsulfinyl, (50) phenylsulfinyl, (51) C₁₋₆ alkylsulfonyl, (52)phenylsulfonyl and (53) 5- or 6-membered heterocyclic group containing 1to 4 hetero atoms selected from oxygen, sulfur and nitrogen, which maybound through one or two atomic chain containing oxygen, sulfur,nitrogen and carbon, in which any group having a carbon chain of 2 ormore carbon atoms or a cyclic group may be further substituted with oneor two substituents selected from the group consisting of (a) halogen,(b) hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e) di-C₁₋₄ alkylamino, (f)halo-C₁₋₄ alkyl, (a) C₁₋₄ acyl, (h) hydroxy-C₁₋₄ alkyl, (i) C₁₋₄alkoxy-C₁₋₄ alkyl, (j) cyano, (k) thioxo and (l) C₁₋₄ alkylthio, and inwhich when the substituent mentioned above exists on two ring-formingatoms adjacent to each other, they may bind together to form a ring. 3.A compound or a salt thereof as claimed in claim 1, wherein ring A is a5- or 6-membered unsaturated heterocyclic group comprising 1 to 4hetero-atoms selected from oxygen, sulfur or nitrogen, which may besubstituted with 1 to 5 substituents selected from the group consistingof (1) C₁₋₄ alkyl, (2) C₂₋₄ alkenyl, (3) C₂₋₄ alkynyl, (4) C₃₋₆cycloalkyl, (5) C₅₋₇ cycloalkenyl, (6) C₇₋₁₁ aralkyl, (7) phenyl, (8)C₁₋₆ alkoxy, (9) phenoxy, (10) C₁₋₆ alkanoyl, (11) benzoyl, (12) C₁₋₆alkanoyloxy, (13) carboxyl, (14) C₂₋₇ alkoxycarbonyl, (15) carbamoyl,(16) N-mono-C₁₋₄ alkylcarbamoyl, (17) N-di-C₁₋₄ alkylcarbamoyl, (18)cycloaminocarbonyl, (19) halogen, (20) mono-, di- or tri-halo-C₁₋₄alkyl, (21) oxo, (22) amidino, (23) imino, (24) amino which may beprotected with a group selected from (i) formyl, (ii) C₁₋₆alkyl-carbonyl which may be substituted with halogen atoms, (iii) C₆₋₁₀aryl-carbonyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (iv) C₁₋₆ alkyloxycarbonyl which may besubstituted with 1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitrogroup, (v) C₆₋₁₀ aryloxycarbonyl which may be substituted with 1 to 3halogen atoms, C₁₋₆ alkylcarbonyl or nitro group, (vi) C₇₋₁₂aralkyl-carbonyl which may be substituted with 1 to 3 halogen atoms C₁₋₆alkylcarbonyl or nitro group, (vii) trityl which may be substituted with1 to 3 halogen atoms, C₁₋₆ alkylcarbonyl or nitro group and (viii)phthaloyl which may be substituted with 1 to 3 halogen atoms, C₁₋₆alkylcarbonyl or nitro group, (25) mono-C₁₋₄ alkylamino, (26) di-C₁₋₄alkylamino, (27) 3- to 6-membered cycloamino which may contain 1 to 3hetero atoms selected from oxygen, sulfur and nitrogen, (28) C₁₋₆alkanamido, (29) benzamido, (30) carbamoylamino, (31) N—C₁₋₄alkylcarbamoylamino, (32) N,N-di-C₁₋₄ alkylcarbamoylamino, (33) C₁₋₃alkylenedioxy, (34) —B(OH)₂, (35) hydroxy, (36) epoxy, (37) nitro, (38)cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43)dihydroxypolyol, (44) sulfamoyl, (45) mono-C₁₋₆ alkylsufamoyl, (46)di-C₁₋₄ alkylsulfamoyl, (47) C₁₋₆ alkylthio, (48) phenylthio, (49) C₁₋₆alkylsulfinyl, (50) phenylsulfinyl, (51) C₁₋₆ alkylsulfonyl (52)phenylsulfonyl and (53) 5- or 6-membered heterocyclic group containing 1to 4 hetero atoms selected from oxygen, sulfur and nitrogen, which maybound through one or two atomic chain containing oxygen, sulfur,nitrogen and carbon, in which any group having a carbon chain of 2 ormore carbon atoms or a cyclic group may be further substituted with oneor two substituents selected from the group consisting of (a) halogen,(b) hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e) di-C₁₋₄ alkylamino, (f)halo-C₁₋₄ alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄ alkyl, (i) C₁₋₄alkoxy-C₁₋₄ alkyl, (j) cyano, (k) thioxo and (l) C₁₋₄ alkylthio, and inwhich when the substituent mentioned above exists on two-ring formingatoms adjacent to each other, they may bind together to form a ring. 4.A compound or a salt thereof as claimed in claim 3, wherein said 5- or6-membered unsaturated heterocyclic group is a monocyclic 5- or6-membered unsaturated heterocyclic group comprising 1 to 4 hetero-atomsselected from oxygen, sulfur or nitrogen.
 5. A compound or a saltthereof as claimed in claim 3, wherein said 5- or 6-membered unsaturatedheterocyclic group is a pyridyl group.
 6. A compound or a salt thereofas claimed in claim 1, wherein R¹ is a hydrogen atom.
 7. A compound or asalt thereof as claimed in claim 6, wherein R¹ is a C₁₋₄ alkyl group, ormono-, di- or trihalo-C₁₋₄ alkyl group.
 8. A compound or a salt thereofas claimed in claim 7, wherein R¹ is a C₁₋₄ alkyl group.
 9. A compoundor a salt thereof as claimed in claim 1, wherein R² and R³ areindependently selected from the group consisting of a hydrogen atom, ahalogen atom, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, phenoxy, C₁₋₄ alkylthio orphenylthio group, wherein the alkyl, alkoxy or alkylthio may have one ortwo substituents selected from the group consisting of (a) halogen, (b)hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e) di-C₁₋₄ alkylamino, (f) halo-C₁₋₄alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄ alkyl, (i) C₁₋₄ alkoxy-C₁₋₄alkyl, (j) thioxo, (k) sulfide, (l) C₃₋₆ cycloalkyl and (m) mercapto, orwhen taken together, R² and R³ represent ═S.
 10. A compound or a saltthereof as claimed in claim 9, wherein R² and R³ are independentlyselected from the group consisting of a hydrogen atom or a C₁₋₄ alkylwhich may have one or two substituents selected from the groupconsisting of (a) halogen, (b) hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e)di-C₁₋₄ alkylamino, (f) halo-C₁₋₄ alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄alkyl, (i) C₁₋₄ alkoxy-C₁₋₄ alkyl, (j) thioxo, (k) sulfide, (l) C₃₋₆cycloalkyl and (m) mercapto.
 11. A compound or a salt thereof as claimedin claim 9, wherein R² and R³ taken together represent ═S.
 12. Acompound or a salt thereof as claimed in claim 1, wherein R⁴ and R⁵ areindependently selected from the group consisting of a hydrogen atom, ahalogen atom, C₁₋₄ alkyl or C₆₋₁₀ aryl group wherein the alkyl or arylmay have one or two substituent groups selected from the groupconsisting of (a) halogen, (b) hydroxy, (c) oxo, (d) C₁₋₄ alkoxy, (e)di-C₁₋₄ alkylamino, (f) halo-C₁₋₄ alkyl, (g) C₁₋₄ acyl, (h) hydroxy-C₁₋₄alkyl and (i) C₁₋₄ alkoxy-C₁₋₄ alkyl.
 13. A compound or a salt thereofas claimed in claim 12, wherein R⁴ and R⁵ are each a hydrogen atom,halogen atom or C₁₋₄ alkyl.
 14. A compound or a salt thereof as claimedin claim 1, wherein R⁶ is a hydrogen atom or a hydrocarbon residueselected from the group consisting of C₁₋₁₅ alkyl, C₆₋₁₄ aryl and C₇₋₁₆aralkyl, each of which may have one to five substituent groups selectedfrom the group consisting of (1) nitro, (2) hydroxy, (3) oxo, (4)thioxo, (5) cyano, (6) carbamoyl, (7) carboxyl, (8) C₁₋₄ alkoxycarbonyl,(9) sulfo, (10) halogen, (11) C₁₋₄ alkoxy, (12) phenoxy, (13)halophenoxy, (14) C₁₋₄ alkylthio, (15) phenylthio, (16) C₁₋₄alkylsulfinyl, (17) C₁₋₄ alkylsulfonyl, (18) amino, (19) C₁₋₆ acylamino,(20) mono- or di-C₁₋₄ alkylamino, (21) C₁₋₄ acyl, (22) benzoyl, (23) 5-or 6-membered heterocyclic group containing one to four hetero-atomsselected from the group consisting of oxygen, sulfur and nitrogen, whichmay be substituted by one to four substituents selected from the groupconsisting of (a) halogen, (b) C₁₋₄ alkyl and (c) halophenoxy, and (24)C₁₋₁₀ haloalkyl, and where the hydrocarbon group is aryl or aralkyl,each of which may have one to four C₁₋₄ alkyl group.
 15. A method forpreparing a compound of the formula:

wherein A, X and R¹-R⁶ are as defined in claim 1, said method comprisescyclizing the compound of the formula:

wherein R⁷ is optionally protected amino group and L is an alkyl oracyl.
 16. An antiprotozoal composition comprising an effective amount ofa compound according to claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier, excipient or diluent.17. The composition as claimed in claim 16, wherein said protozoa iscoccidia.
 18. An animal feed additive premix comprising a compoundaccording to claim 1 or a physiologically acceptable salt thereof.
 19. Amethod for inhibiting protozoa in an animal which comprisesadministering an effective amount of the compound according to claim 1or a physiologically acceptable salt thereof to said animal.
 20. Themethod as claimed in claim 19, wherein said animal is a bird.
 21. Amethod for breeding an animal which comprises administering the compoundaccording to claim 1 or a physiologically acceptable salt thereof tosaid animal.